MIMs - Handbook of General Medicine 2019

TREATMENT APPROACHES 143

Management and prevention of malaria Treatment approaches

LH Blumberg Laboratory diagnosis of malaria

MBBCh MMed (Micro) ID (SA) FFTM (RCPS,Glasgow) DTM&H Treatment should ideally be based on a confirmed par-
DOH DCH asitological diagnosis. Early diagnosis leading to prompt
treatment is required to minimise malaria morbidity and
National Institute for Communicable Diseases, mortality. The traditional method of malaria diagnosis is
University of Stellenbosch, Stellenbosch the microscopy of blood smears stained with Giemsa
(or similar stains). The World Health Organization states
J Frean that “The detection of malaria parasites by light micros-
copy remains the reference method for diagnosis of
MBBCh, MMed (Path Microbiol), DTM&H malaria throughout the world”. This applies particularly
to diagnosis for case management in endemic areas.
National Institute for Communicable Diseases, Good microscopy requires skill and experience, good
division of National Health Laboratory Service, quality reagents and equipment, and regular quality
Johannesburg, Wits Research Institute assessment. When done optimally, the advantages of
for Malaria, University of the Witwatersrand, Johannesburg microscopy are cheap consumables, accurate para-
site species and load determination, and the ability to
L Baker detect other blood parasites, e.g. trypanosomes and
microfilariae incidentally. There is also the possibility of
Dip Pharm storing stained films as a permanent record. Microsco-
py’s disadvantages are that it is time-consuming, and
Amayeza Info Services, Johannesburg requires intensive training, technical expertise, and rela-
tively expensive equipment in the form of microscopes
The majority of cases of malaria in sub-Saharan Africa that require care and maintenance.
are due to infection with Plasmodium falciparum, the
species associated with the most severe disease. De- Rapid diagnostic tests (RDTs), based on lateral-flow
spite the availability of highly sensitive diagnostic tests immunochromatographic detection of malaria anti-
and effective drugs, malaria is associated with signifi- gens in point-of-care devices, are suitable for use by
cant morbidity and mortality because of misdiagnosis persons without specific laboratory training, where mi-
and treatment delays. It is critical always to have a high croscopy is not readily available. (Note, however, that
index of suspicion for malaria in travellers to, or residents training in the use of rapid tests themselves is essential.)
of, malaria-transmission areas presenting with fever or a As in many countries, RDTs are the mainstay of diagnosis
’flu-like illness, irrespective of the time of year, the inten- in primary health clinics and centres in South African
sity of transmission or use of chemoprophylaxis. Given malaria-transmission areas. Most commercially availa-
the non-specific presentation of malaria, an accurate ble RDTs detect the P. falciparum histidine-rich protein 2
travel history is critical and must prompt urgent testing. (PfHRP-2) antigen (and, usually, PfHRP-3 to some extent);
tests for pan-specific antigens, such as lactate dehydro-
The typical presentation of malaria in adults is an genase or aldolase will detect other species. Apart from
acute onset of fever with paroxysms of fever, rigours the advantage of speed (15 to 20 minutes until reading,
and myalgia. Loss of appetite, nausea and vomiting, which is shortened by the user as is often done, may
and fatigue may also be noted. In young children, fe- yield false negatives), the HRP-2-based tests have ade-
ver, lethargy, poor feeding, vomiting and diarrhoea are quate sensitivity, compared with average microscopy
most common. Influenza is the most common misdiag- ability. Disadvantages are that RDTs may remain posi-
nosis of malaria due to overlapping clinical symptoms tive for some weeks after successful treatment, so can-
of fever, rigours and myalgia. Considering specific travel not be used to monitor response to treatment. Some P.
and exposures, the differential diagnosis of an acute fe- falciparum strains have gene deletions that prevent the
brile illness would also include African tick-bite fever, ty- expression of the target HRP-2/3 antigens (particularly
phoid, a viral haemorrhagic fever, leptospirosis, Q fever in South America and West Africa, but to date this has
and trypanosomiasis. The diagnosis of malaria is most not been a problem in southern Africa). Very high an-
frequently missed in patients with comorbid disease and tigen levels can cause false-negative results because
those at the extremes of age. Malaria is frequently mis- of prozone effects, and pan-specific antigen tests may
diagnosed in pregnancy, requiring differentiation from have a lower sensitivity. Parasite load quantitation is not
pregnancy complications, including intra-uterine and possible, and non-malarial parasite blood infections will
urinary tract infections. Examination of patients with sus- not be detected. Finally, there is substantial variation
pected malaria is critical to identify clinical signs that in quality between various manufacturers, and device
would suggest severe disease rapidly. The presence of stability in hot climates can be a problem.
any change in the mental state, jaundice and/or res-
piratory distress in any person resident in, or with recent Fluorescence microscopy techniques have been
travel to a malaria-transmission area, must prompt ur-
gent laboratory testing and resulting, given that these HANDBOOK OF GENERAL MEDICINE VOL 1
are criteria for severe malaria.

Progression to severe disease may be rapid, particu-
larly in non-immune and immune-compromised per-
sons, young children and pregnant women.

144 TREATMENT APPROACHES

developed, mainly to speed up and simplify the micros- then become important tools for detecting and treat-
copy process. Acridine orange (AO) staining of smears ing the reservoirs of infection in communities. Molecular
is one such technique; another is the quantitative buffy methods are ideal for monitoring the development of
coat (QBC) method, which concentrates and stains antimalarial drug resistance before it becomes clinically
with AO the parasitised cells in a centrifuged micro- problematic, by looking for known DNA mutation mark-
haematocrit tube of blood. The tube is then examined ers associated with resistance.
under ultraviolet light, using a long, focal-length objec-
tive in a fluorescence microscope. In theory, the tech- Malaria serology (testing for antibodies) has no place
nique improves the sensitivity of microscopy, compared in routine acute diagnosis; it is useful only to detect prior
with standard blood film microscopy. However, these exposure in blood donors (in some countries, not South
fluorescence methods are not used in public-sector Africa) or suspected hyperreactive malarious spleno-
laboratories in South Africa. megaly, or in epidemiological surveys, where it can pro-
vide a measure of burden of infection in a community
Molecular techniques, such as PCR, are normally time- over an extended period.
consuming and not suitable for routine diagnostic use
for malaria (malaria diagnosis being an emergency), Table 1 lists the essential clinical practice points on
but rather for epidemiological surveillance and parasi- malaria diagnosis.
tological research purposes, and for reference lab use
to confirm difficult (e.g. rare or mixed species) identifi- Treatment of malaria
cation, or to confirm malaria after drug treatment has
been given, when parasites may not be detectable by The choice and route of treatment depend primarily
microscopy. The advantages of PCR are high sensitivity on disease severity, which is often underestimated. Un-
and specificity compared with older methods, but at a complicated malaria is symptomatic infection without
higher cost because of the transport logistics, special- signs of severity or evidence of vital organ dysfunction.
ised equipment and reagents, and laboratory staff and Persistent vomiting, prostration, clinical jaundice, any
facilities required to produce reliable results. Unless there change in mental state, and/or an increase in respira-
is meticulous attention to detail, contamination lead- tory rate constitutes severe malaria (see Table 2).
ing to false positives is a risk. The advent of automated
DNA extraction and real-time PCR may speed up the All patients, including young children and pregnant
processing time, but the expense is likely to remain a women with uncomplicated malaria, must be treated
constraint for widespread use of PCR. A variation of the with artemether-lumefantrine (Coartem®) (see Table 3).
technique, called loop-mediated amplification (LAMP), Oral quinine combined with doxycycline is poorly toler-
is less technically demanding than PCR, and more ated and compliance is a problem.
suited to field or near-field use in epidemiological sur-
veys, but is still expensive. As control measures reduce For optimal absorption, artemether-lumefantrine must
malaria incidence to the point at which elimination be taken with full-cream milk or fat-containing food.
becomes feasible, more sensitive methods of detect- Adequate fluids, temperature control with paracetamol,
ing infection than microscopy and RDTs (i.e. diagnosing and careful follow-up are important. Avoid nonsteroidal
submicroscopic infections) are required. PCR and LAMP anti-inflammatory agents. Patients should respond clini-
cally and parasitologically within 24-48 hours. Consider
poor compliance, failure to administer drugs with fatty
food, "underdosing" (especially if patients are >80 kg),

Table 1. Essential clinical practice points on malaria diagnosis

• The diagnosis of malaria is a medical emergency
• Malaria cannot be diagnosed or excluded on clinical grounds.
• Urgent testing by RDT or laboratory methods is mandatory in any patient with a febrile illness compatible with malaria, with

or without an appropriate travel history.
• This is irrespective of the time of the year and history of chemoprophylaxis use.
• Prophylaxis and antibiotic use may prolong the incubation period and suppress the malaria parasite level below the

detectable limit.
• A negative malaria test does not exclude the diagnosis.
• If malaria is suspected, tests should be repeated at appropriate intervals (12-24 hours) without attempting to coincide with

fever peak timing, until a positive result is reported or an alternative diagnosis is made.
• If the patient is critically ill, empiric treatment may be warranted while laboratory confirmation is awaited.
• Personally follow up results actively and do not assume they will automatically reach you.
• Quantitation of P. falciparum parasite load, as an indication of severity or of response to treatment, should be routinely

reported as part of the microscopic smear examination.
• Rapid antigen tests may occasionally give false-positive or false-negative results; stained smear examination should be done

as well when possible, especially if clinical suspicion of malaria is high.
• Do not request PCR alone for primary diagnosis, particularly if the patient is very ill, as it may take days to get the result;

standard microscopy or RDTs are much quicker.
• Malaria must be considered in any person with unexplained fever and progressive illness. Odyssean malaria or “axi malaria”

is an uncommon phenomenon, but has a high mortality, given the delays in diagnosis. Thrombocytopaenia is a common
laboratory finding even in uncomplicated malaria and must always prompt an examination of the blood for malaria
parasites in patients with unexplained fever.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 145

Table 2. Clinical and laboratory criteria for severe malaria (any one or combination of these criteria applies) Treatment approaches

Clinical
• Prostration
• Repeated vomiting
• Impaired consciousness, multiple convulsions( >2 within 24 hours), coma
• Respiratory distress, acidotic breathing, pulmonary oedema
• Circulatory collapse
• Anuria
• Jaundice
• Abnormal bleeding

Laboratory

• Hypoglycaemia (blood glucose <2.2 mmol/L)
• Acidosis (plasma bicarbonate <15 mmol/L or serum lactate >5 mM)
• Hepatic transaminases >3 times normal, jaundice ( Br >50 µM)
• Renal impairment (serum creatinine >265 µmol/L or blood urea >20 mmol/L or rapidly rising creatinine or urine output <400 mL/

day in an adult)
• Haemoglobin <7 g/L
• Parasitaemia ≥5%
• ≥ 5% neutrophils contain malaria pigment
• Presence of schizonts of P. falciparum in peripheral blood smear

possible drug resistance or misdiagnosis if no significant pharmacokinetic data exist for larger patients; one
improvement occurs within 72 hours. Artemether-lume- study suggests a trend towards increased risk of treat-
fantrine remains efficacious in South Africa (SA). Arte- ment failure in patients >80 kg. Again, adequate ad-
misinin-resistant parasites have not yet been found in herence and fat co-administration are essential, with
SA and are rarely found in sub-Saharan Africa. In the careful monitoring of response. Extending the course of
rare event of artemether-lumefantrine treatment fail- artemether-lumefantrine to five days (twice-daily dose)
ure, despite full compliance, alternative therapy using is a consideration, but data on efficacy are lacking.
oral quinine plus doxycycline or atovaquone-proguanil
plus mefloquine should be considered. Either culturing Recommendations for non-falciparum
or molecular characterisation of these infections is re- malaria
quired to confirm the presence of artemisinin-resistant
parasite strains. Malaria species should be confirmed by a reliable lab-
oratory. Non-falciparum infections are usually uncom-
Drug interactions plicated, but occasionally produce severe illness. Use
artemether-lumefantrine for initial therapy of uncompli-
Concomitant use of certain other drugs (e.g. efa- cated P. vivax and P. ovale infections. To prevent relaps-
virenz, rifampicin) may alter blood concentrations of es, this should be followed by a course of primaquine
artemether-lumefantrine and quinine. There is no evi- after excluding glucose-6-phosphate dehydrogenase
dence of the clinical significance of these interactions, (G6PD) deficiency. P. malariae infections are uncom-
but full adherence and fat co-administration are ad- mon, typically cause mild illness, are non-relapsing, and
vised, and response to treatment should be monitored respond well to artemether-lumefantrine. P knowlesi,
particularly carefully. a zoonotic parasite, has been reported in persons in
South-East Asia.
Pregnancy: Artemether-lumefantrine should be used
for uncomplicated malaria in all trimesters. However, Severe malaria
even pregnant woman with uncomplicated malaria
should ideally be admitted to hospital and carefully ob- Severe malaria is a medical emergency requiring
served for complications, especially hypoglycaemia. prompt parenteral treatment, intensive nursing care,
and careful monitoring and management of complica-
Large adults: Artemether-lumefantrine is registered tions. Intravenous artesunate is the treatment of choice
in SA only for use in patients weighing ≤65  kg. Minimal

Table 3. Dosing schedule for artemether-lumefantrine

Body weight (kg) Time of dosing (hours) and number of tablets

5-14 0 8-12 24 36 48 60
15-24 1
25-34 11111 2
≥35 3
22222 4

33333

44444

HANDBOOK OF GENERAL MEDICINE VOL 1

146 TREATMENT APPROACHES

Table 4. General guidelines for fluid management in severe malaria

Clinical status Adults Children

No severe dehydration, no anuria, no Initial: 0.9% saline intravenous (IV) Initial: 0.9% saline IV 3-5 ml/kg per h for
shock 2-4 ml/kg per hour for 6 hrs 3-4 h
Maintenance: 5% dextrose/0.9% Maintenance: 5% dextrose IV 2-3 ml/kg
saline IV 2-3 ml/kg per hour per h
Monitoring: every 2 hrs for the first 6 hours Monitoring: every 2 h for the first 6 h

Severe dehydration, urine output Initial: 0.9% saline IV 10 ml/kg per h for 2 h
<0.5 mL/kg per hour If no urine output (>0.5 ml/kg per h)
response:
Repeat: 5% dextrose/0.9% saline IV
5 ml/kg per h for 4 h
Monitoring: every 2 h

Adapted from Plewes, et al. Malaria: What’s new in the management of malaria? Infect Dis Clin North Am. 2019 Mar;33(1):39-60.doi:10.1016/j.
idc.2018.10.002

and is registered in South Africa as Garsun®. Artesunate as acute respiratory distress syndrome (ARDS) is a com-
should be used for all patients with any clinical or labora- mon and difficult-to-treat complication, particularly in
tory indicator of severe malaria. There is no lower age pregnancy. Early dialysis, ideally using renal replace-
or weight for use in children. Artesunate should be used ment therapy, is critical.
in all trimesters of pregnancy, given the severity of illness
and major advantages of artesunate, as detailed below. Hypoglycaemia
Artesunate should always be given for a minimum of 24
hours at 0, 12 and 24 hours, then daily until the patient Urgently exclude hypoglycaemia (or administer empiric
can tolerate oral treatment (dosing <20  kg at 3.0  mg/ glucose) if there is a depressed level of consciousness or
kg; >20 kg at 2.4 mg/kg). Due to its action against both convulsions. Repeat glucose-monitoring 4-hourly.
young and older trophozites, artesunate has been shown
to reduce malaria mortality significantly. Compared to Broad-spectrum antibiotics
quinine, artesunate is well tolerated, does not cause
hypoglycaemia and does not require dose modifica- Administer to children with severe malaria, given the fre-
tion in renal failure. Artesunate is prepared according quent presence of bacterial septicaemia.
to the manufacturer’s instructions and is administered
over a few minutes, a major advantage in busy hospi- There is no evidence to support the use of steroids,
tal wards, as compared to the slow infusion of quinine mannitol, desferrioxamine, or exchange transfusions.
over four hours. Post-artesunate, delayed-onset hae-
molysis of once-infected red blood cells is an expected Prevention of malaria
consequence of the removal of pyknotic ring-form para-
sites through splenic pitting after artesunate treatment. The mainstay of malaria prevention is ensuring that one
All patients must complete a full course of artemether- does not get bitten by the infected mosquitoes. Mos-
lumefantrine to comply with the need for combination quitoes that transmit malaria generally bite at night,
therapy and to prevent recrudescence. and therefore people in a malaria area should ideally
remain indoors between dusk and dawn, and sleep un-
Critical issues in management of severe malaria der insecticide-treated bednets in rooms with screens
on the windows and doors.
All patients with severe malaria must be treated in the
highest level of care available in the hospital and must Travellers, in particular, need to know what the risk
be reassessed frequently to ensure that complications of contracting malaria is in the area to which they are
are promptly detected and optimally managed. travelling. In South Africa, the risk areas have changed
slightly in recent years and an updated map was pub-
Fluids lished at the end of 2018 (see Figure 1).

In patients with shock, clinical dehydration and/or Travellers and residents in these risk areas should take
acidosis, initial fluid therapy using crystalloid should be measures to prevent being bitten by mosquitoes.
administered, as detailed in Table 4. Boluses of fluid are
not recommended. Effective repellents include those containing 20-50%
DEET (diethyl toluamide) or picaridin (icaridin) 20%.
Acute kidney injury complicates up to 40% in adults, These are safe for all persons from two months of age,
and 10% of paediatric falciparum malaria. Severe ma- including pregnant women, provided they do not have
laria requires careful fluid management, with frequent an allergy to the ingredients.
measurement of renal function (urea, electrolytes and
creatinine), ongoing monitoring of urine output and ju- In addition to these measures, and depending on the
dicious fluid administration. Strictly avoid over-hydration, risk, travellers should also take appropriate chemopro-
phylaxis. The National Department of Health recom-
HANDBOOK OF GENERAL MEDICINE VOL 1 mends three agents, and they are considered to be
equally effective, at around 90%, and the choice of
which one to recommend depends on the traveller’s
health factors and which option is likely to be best toler-

TREATMENT APPROACHES 147

Treatment approaches

Figure 1. Updated South African Malaria Risk Map 2018 medication, it is important to prescribe appropriate in-
dividualised chemoprophylaxis. No dosage reduction is
ated for optimal adherence. This choice has, however, required based on advanced age, but in some instanc-
been significantly limited, in that there are currently no es, there is no ideal option, and the traveller should be
mefloquine-containing products available in South Af- made aware of the risks.
rica. This means that there is currently no product that
can be used for pregnant travellers or children weigh- Renal impairment: A-P is contraindicated in travellers
ing less than 11 kg. As these are also the travellers at with a creatinine clearance <30 ml/min; doxycycline is
the highest risk of complicated malaria, they should be an option.
strongly advised not to go to malaria-risk areas. If they • Travellers on oral anticoagulants: Both A-P and doxy-
have no option but to go, they should use all methods
available to prevent getting bitten by mosquitoes and cycline have the potential to interact with warfarin. It
should seek immediate medical attention should they is important for travellers to start taking the antimalar-
have any signs of illness. ials a few weeks before leaving and to monitor their
INR carefully and adjust the dose, if necessary. There
The other two options for chemoprophylaxis are is a lack of information regarding the new oral anti-
atovaquone-proguanil (A-P) and doxycycline, both coagulants.
of which are now available from pharmacies with- • Cardiac conditions: Either A-P or doxycycline can be
out a doctor’s prescription. Paediatric preparations of given.
atovaquone-proguanil (Malanil Paediatric®) can be • Diabetics: Monitor blood-glucose levels regularly.
used in children >11 kg. • Travellers taking antacids: Absorption of doxycycline
is reduced if taken concurrently. Preferably, use A-P
Table 5 overleaf lists the profiles of available chemo- or administer doxycycline at least two hours before,
prophylaxis or four to six hours after antacids.
For full guidelines, see South African Guidelines for the
Focus on the elderly Prevention of Malaria – updated in 2019 and available
at www.santhnet.co.za
The risk of developing severe malaria, once infected, Whatever chemoprophylaxis is used, it is important
is higher in certain risk groups, including the elderly, es- to take the doses regularly and to finish the course.
pecially in those over the age of 70 years. Due to an in-
creased incidence of underlying disorders, such as renal HANDBOOK OF GENERAL MEDICINE VOL 1
impairment, and the likelihood of their taking chronic

148 TREATMENT APPROACHES

Table 5. Profiles of available chemoprophylaxis

Atovaquone-proguanil Doxycycline
Cyclidox® and Doxycyl®
Available products Malanil®, Mozitec® and Malateq® 100 mg daily, starting the day before entering the
malaria area, daily while there and daily for four
Dose: adults 1 adult tablet = 250 mg atovaquone plus 100 mg weeks after leaving the area
proguanil
1 tablet daily, starting the day before entering the From 8 years of age only
malaria area, daily while there and daily for seven 2 mg/kg daily, as for the adults
days after leaving the area
• A good option for the last-minute traveller
Dose: children 1 paediatric tablet = 62.5 mg atovaquone plus • No documented resistance
25 mg proguanil (Malanil Paediatric ®) from 11 kg • Can be used for two or more years
weight. It is not possible to divide a tablet to • The best option for travellers who are HIV+ve
accommodate the dosage in children <11 kg
11-20 kg: 1 paediatric tablet daily and on antiretrovirals
21-30 kg: 2 paediatric tablets daily • The best option for travellers taking rifampicin
31-40 kg: 3 paediatric tablets daily
>40 kg: 1 adult tablet daily • Contra-indicated in pregnant women and
children less than eight years of age
Advantages • The only option for children under 8 years of age
and who weigh more than 11 kg • Should only be used while breastfeeding if there
is no other option
• A good option for the last-minute traveller
• A good option for short-term travel • Must be taken for four weeks after leaving the
• Well tolerated, with few side effects area
• Very few contra-indications
• No known resistance • Has to be taken daily. It is very unforgiving, and
• Effective against all species (but not the if a dose or two is missed, prophylactic failure
may occur
hypnozoite stage of P. vivax and P. ovale
• Can be used for up to one year and even • Use with caution in travellers who have
myasthenia gravis
longer if justified by the risk of exposure
• Take note of normal drug interactions,
Disadvantages • Should not be given to pregnant or especially with anticonvulsants, such as
breastfeeding women as there is a lack of phenytoin, phenobarbitone and carbamazepine
information regarding its safety
• Side effects experienced include photosensitivity,
• Not indicated for children weighing less vaginal candidiasis and gastro-intestinal effects,
than 11 kg particularly oesophagitis, if not taken correctly

• It may interact with certain antiretrovirals • Prophylactic failure may occur if the traveller has
• Contra-indicated in travellers with severe renal diarrhoea or vomiting

impairment
• Must be taken daily
• Headache, mouth ulcers and abdominal pain

are the most frequently reported side effects
• Has to be taken daily

However, even if taken correctly, no prophylaxis is 100% 4. Frean J, Poonsamy B, Shandukani B, et al. Case management of
effective, and there is still a small risk of the traveller con- malaria: Diagnosis. South African Medical Journal. 2013;103(10 Sup-
tracting malaria. Therefore, it is critically important for pl 2):789-793. DOI: 10.7196/SAMJ.7442
the traveller to seek immediate medical attention if he
or she experiences any signs of illness, especially ‘flu-like 5. Frean J, Brooke B, Thomas J, Blumberg L. Odyssean malaria out-
symptoms, from seven to 10 days after arriving in the breaks in Gauteng Province, South Africa, 2007-2013. SAMJ.
malaria area and for six months after leaving the area. 2014;104(5):335-338. doi:10.7196/samj.7684.

further reading 6. Taylor SA, Parobek CM, DeConti DK, et al. Absence of putative ar-
temisinin resistance mutations among Plasmodium falciparum in
1. Plewes K, Leopold SJ, Kingston HWF, et al. Malaria: What’s new sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis.
in the management of malaria? Infect Dis Clin North Am. 2019 2014;211:680-8.
Mar;33(1):39-60. doi: 10.1016/j.idc.2018.10.002
7. South African Guidelines for the Prevention of Malaria. http://www.
2. South African National Department of Health. Guidelines for the nicd.ac.za/wp-content/uploads/2017/09/Guidelines-South-Afri-
treatment of malaria in South Africa. Pretoria: NDoH, 2018. http:// can-Guidelines-for-the-Prevention-of-Malaria-2017-final.pdf (ac-
www.health.gov.za/index.php/guidelines-policies (accessed 16 cessed 16 January 2019)
January 2019)
8. Dondorp A, Nosten F, Stepniewska K, et al. SEAQUAMAT Trial Group.
3. World Health Organization. Malaria Microscopy Quality Assurance Artesunate versus quinine for treatment of severe falciparum ma-
Manual. WHO: Geneva, 2016. laria: a randomized trial. Lancet. 2005;366:717-25

HANDBOOK OF GENERAL MEDICINE VOL 1 9. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus
quinine in the treatment of severe falciparum malaria in African
children (AQUAMAT): an open label, randomised trial. Lancet.
2010;376:1647-57

TREATMENT APPROACHES 149

10. Esu E, Effa EE, Opie ON, et al. Artemether for severe malaria. Treatment approaches
Cochrane Database Syst Rev. 2014;(9):CD010678

11. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in Af-
rican children with severe infection. N Engl J Med. 2011;364:2483-95

12. Church J, Maitland K. Invasive bacterial co-infection in African
children with Plasmodium falciparum malaria: a systematic review.
BMC Med. 2014;12:31-47

13. Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin
derivatives and quinine treatments and the risk of adverse preg-
nancy outcomes in Africa and Asia: A meta-analysis of observa-
tional studies. PLoS Med. 2017;14: e1002290.

14. Chiodini PL, Patel D, Whitty CJM, et al. Guidelines for malaria pre-
vention in travellers from the United Kingdom, 2017. London: Public
Health England; October 2017.

15. Tan KR, Magill AJ, Parise ME, et al. Doxycycline for malaria chemo-
prophylaxis and treatment: Report from the CDC expert meeting on
malaria chemoprophylaxis. Am J Trop Med Hyg. 2011;84(4),517-531

16. Tickell-Painter M, Maayan N, Saunders R, et al. Mefloquine for pre-
venting malaria during travel to endemic areas. Cochrane Data-
base of Systematic Reviews. 2017; Issue 10. Art. No.: CD006491

17. HIV Drug Interactions. University of Liverpool. https://www.hiv-
druginteractions.org (accessed 20/01/2019)

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150 TREATMENT APPROACHES

Rabies: prevention and management

J Weyer virus is described from herpestid species. This most com-
monly includes yellow mongoose and is often referred
(PhD, MPH) to as “mongoose" or "meerkat” rabies. Rabies is repor-
ted in various domestic and wildlife animal species in
Centre for Emerging Zoonotic and Parasitic Diseases, South Africa.6 (see Table 1).
National Institute for Communicable Diseases, Johannesburg
The occurrence of rabies in specific animal species
LH Blumberg in South Africa varies geographically. For example, in
the Western Cape province, rabies is almost exclusively
MBBCh MMed (Micro) DTM&H DOH DCH reported from bat-eared foxes and no human cases of
the disease have been reported from this province.6,7
Centre for Emerging Zoonotic and Parasitic Diseases, Rabies in domestic dogs predominates in urban and
National Institute for Communicable Diseases, Johannesburg peri-urban settings where the presence of sufficient
numbers of unvaccinated dogs may sustain outbreaks
The rabies virus causes fatal encephalitis in humans and of the disease. Although dog-transmitted rabies is en-
animals, and there is no treatment once symptoms of demic in South Africa, the epidemiology of the disease
the disease develop. It is estimated that up to 59 000 is dynamic, and outbreaks of rabies in dogs (and other
human cases of rabies globally occur on an annual species) are reported intermittently in locations where
basis.1 This equates to a human rabies death every 10 the disease was either never reported before or pre-
minutes. Nearly all human cases are reported from Afri- viously controlled.8,9 When presented with a possible
can and Asian countries, where rabies in domestic dogs rabies-exposure case, it is important to consider the oc-
has not been controlled1. Nearly all human rabies cases currence of rabies in a particular animal species in a
are associated with dog exposures.1 A One Health ap- given geographical location. This information could be
proach to prevention is key; vaccination of dogs and accessed via a local state veterinarian or the National
cats is critical in preventing human cases. Post-exposure Institute for Communicable Diseases could be contact-
prophylaxis (PEP) for humans, if given timeously and ac- ed for assistance.
cording to international guidelines, is highly effective in
preventing disease in exposed persons.2 These biologi- In South Africa, human rabies cases (both suspected
cals are expensive and access is generally limited.2 and confirmed) are notifiable. Suspected human rabies
cases are subject to laboratory investigation by the Na-
The disease is caused by virus species belonging to tional Institute for Communicable Diseases. Between
the genus Lyssavirus and family Rhabdoviridae.3 Cur- five and 11 human rabies cases have been laboratory-
rently, 16 species are formally classified as lyssaviruses.3 confirmed in South Africa every year since 1981, and the
The lyssaviruses are a fast expanding group of viruses, number of cases directly correlates with the prevalence
with nine of the viruses being discovered and described of rabies in domestic dogs in areas around the country.6
in the past 15 years.4 This is primarily due to increased More than 70% of these cases are reported in children
surveillance of novel pathogens in bat species around and teenagers, a characteristic of rabies also recognised
the globe.4 However, the public health burden of rabies elsewhere where dog rabies is still the main concern.7
globally remains the rabies virus (previously designated
as genotype one lyssavirus) transmitted by domestic Pathobiology and clinical
dogs.1 The remaining lyssaviruses are mostly associated presentation of rabies
with bat reservoirs (except the Mokola and Ikoma lys-
saviruses which have been described from different The incubation period for rabies virus is 20-90 days, al-
wildlife species in African countries) and only a handful though rare cases have been reported involving shorter
of human cases have been ascribed to infection with or longer incubation periods.10-11 The virus is introduced
these rabies-related viruses.5 into the body through the virus-laden saliva of a rabid
animal. This may be delivered through any breach of
Rabies in South Africa the skin, including bites, scratches and nicks. Wounds
do not have to be large or deep; any break of the skin
In South Africa, rabies has been recorded through- may present a possible route for entry into the body. A
out the colonial period with the introduction of dog- lick of mucous membranes or already broken skin may
transmitted rabies, which caused transient outbreaks also provide routes of virus entry into the body. Follow-
during this time. Dog rabies was established in South ing exposure, the virus undergoes limited amplification
Africa in the 1960s when it was introduced to KwaZulu- at the site of introduction into the body, after which it
Natal province from neighbouring Mozambique. It was will spread in the peripheral nerves to the central ner-
brought under control, but was once again introduced vous system and after that through the nervous system
in this province in the early 1980s and has been reported to the periphery.11-12 During the incubation period, very
ever since.6 Apart from the rabies reported in domes- little is noted clinically, with a few persons complaining
tic dogs and other canids (i.e. bat-eared foxes, black-
backed jackals), a second biotype or biovar of rabies

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Table 1. List of laboratory-confirmed rabies cases in animal species in South Africa, January 2013-June 2018 Treatment approaches

Species Number of confirmed cases

Aardwolf (Proteles cristata) 31

African civet (Civettictis civet) 1

African wild cat (Felis silvestris lybica) 1

Bat-eared fox (Otocyon megalotis) 57

Black-backed jackal (Canis mesomelas) 15

Bovine (domestic cattle) 370

Cape fox (Vulpes chama) 4

Cape clawless otter (Aonyx capensis) 1

Cape ground squirrel (Xerus inauris) 2

Goat (Capra aegagrus hircus) 66

Caracal (Caracal caracal) 3

Common duiker (Sylvicapra grimmia) 4

Domestic cat (Felis catus) 67

Domestic dog (Canis lupus familiaris) 1 089

Equine (domestic horses) 19

Goat (Capra aegagrus hircus) 71

Herpestid, unidentified species 15

Honey badger (Mellivora capensis) 9

Large grey mongoose (Herpestes ichneumon) 8

Ovine (sheep) 26

Rock hyrax (“dassie”, Procavia capensis) 1

Selous’ mongoose (Paracynictis selousi) 1

Serval (Leptailurus serval) 3

Side-striped jackal (Canis adustus) 5

Slender mongoose (Galerella sanguine) 7

Small grey mongoose (Galerella pulverulenta) 8

Small-spotted cat (Felis nigripes) 1

Small-spotted genet (Genetta genetta) 2

Spotted hyena (Crocuta crocuta) 1

Striped pole cat (Ictonyx striatus) 7

Suis (domestic pigs or Sus domesticus) 1

Suricates (species not reported) 7

Water mongoose (Atilax paludinosus) 16

White-tailed mongoose (Ichneumia albicauda) 3

Wild dog (Lycaon pictus) 1

Yellow mongoose (Cynictis penicillata) 49

Data from Department of Agriculture, Forestry and Fisheries, www.daff.gov.za, as available on 7 January 2018

of paraesthesia and pain at the wound site (which is Laboratory investigation of rabies
typically healed already).12 During this period, diag-
nostic tests for rabies are negative. Once clinical symp- in humans
toms develop, the outcome of the infection is irrever-
sible. About two-thirds of patients develop so-called Rabies virus infection does not produce a viraemia and
furious rabies which includes hyper-excitability, gener- there are no specific rabies diagnostic tests that can
alised arousal and in some cases hydrophobia.11-12 The confirm or exclude exposure to the virus. The response
remaining cases present in the paralytic form, which is to possible exposure is always a risk assessment to inform
not unlike Guillain-Barré syndrome.11 Clinical diagnosis the administration of post-exposure prophylaxis (PEP)
is based on the observation of progressive encephalitis (see overleaf). Likewise, following infection and onset
and may be supported when a history of possible expo- of symptoms, routine blood tests are not informative for
sure to a rabid animal is reported. Survival with intensive the diagnosis. Magnetic resonance imaging may pro-
care rarely exceeds one month, and patients ultimately vide some insights, especially for other encephalopa-
succumb to multiple organ failure.11-13 The differential thies,11 computed tomography is typically normal and
diagnosis for rabies is expansive. These may include oth- electroencephalography usually shows diffuse slow-
er causes of viral encephalitis, bacterial meningitis, but wave activity.12 Specialised laboratory testing is always
also non-infectious aetiologies (see Table 2).11-12,14 required to confirm rabies virus infection. Ante-mortem
diagnosis relies on the detection of viral RNA in saliva,
cerebrospinal fluid and/or nuchal biopsies (see Table

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152 TREATMENT APPROACHES

Table 2. Rabies differential diagnosis of infectious aetiology in South Africa14

Diagnosis Clinical presentation Considerations

Tetanus Convulsions on sudden stimuli, trismus, Vaccination history should be considered;
difficulty swallowing (may be confused patient with clear consciousness and no
for hydrophobia which is typical of signs of encephalitis; rabies patients usually
rabies) do not have sustained rigidity of the axial
jaw muscles as with tetanus

Bacterial meningitis High fever, headache, confusion, Abnormal CSF present
sleepiness, irritability, nausea, seizures,
petechial rash

Viral meningitis General encephalitic picture with a rash No obvious behavioural changes, no
lucid periods and no typical spasms,
midline structure involvement on magnetic
resonance imaging. Causative agents
include herpes simplex virus, arboviruses

Cerebritis, encephalitis Impaired consciousness, generalised Malaria, trypanosomiasis, history of travel
convulsions, coma important and confirmatory blood tests

Acute flaccid paralysis, poliomyelitis Weakness, flaccid paralysis Patients have a clear consciousness

3).15 Sensitivity of testing is confounded by several fac- chemical test has been described, which can be used
tors, including the timing of the specimen collection and in more resource-pressed environments for accurate
a history of any rabies vaccination or immunoglobulin post-mortem diagnosis on brain specimens.16
therapy. Specimens from patients who have received
rabies vaccination or immunoglobulin may test nega- Management of rabies virus exposures
tive by PCR.12 The most reliable diagnostic test remains
the detection of rabies virus antigen in brain specimens Rabies can be prevented through the application of
collected post mortem. The direct fluorescent antibody prompt PEP, which involves thorough wound-cleaning,
test is widely used for the diagnosis of rabies in animals followed by the use of rabies vaccine and rabies immu-
and humans. More recently, the direct immunohisto- noglobulin (RIG).2 The guidelines for PEP were revised by
the World Health Organization (WHO) in 2018 to reduce

Table 3. Laboratory tests for the investigation of suspected human rabies cases for ante-mortem and post-mortem diagnosis

Test Specimen/s Interpretations and special considerations Reference

Reverse Saliva Sensitive specimen for ante-mortem investigation. 15
transcription Collect up to three specimens at different time points (preferably, e.g.
PCR day 1, 2, 1) for more sensitive investigation.
Saliva may test negative for the presence of viral RNA due to intermittent
shedding pattern of the virus in the secretion and does not exclude the
diagnosis

Skin biopsy Sensitive specimen for detection of viral RNA from the first day of onset 15
of clinical disease. May be collected ante-mortem or post-mortem.
Specimen with appropriate depth must be collected from the nape of
the neck to include hair follicles.

Cerebrospinal fluid Not the most sensitive specimen for detection of viral RNA ante- 15
mortem. Co-submitted with other specimens for a complete battery of
investigation.

Brain Detection of viral RNA in post-mortem-collected brain specimen. Usually
performed to confirm antigen-detection assays.

Serology Blood Detection of anti-rabies IgG and IgM or virus-neutralising antibodies 11,12
are considered diagnostic in patients who did not receive any rabies
vaccination or rabies immunoglobulin before testing. Not all rabies
patients seroconvert and seroconversion is usually diminished. Not the
most sensitive test for confirming or excluding rabies diagnosis, but
included for a complete battery of testing.

Cerebrospinal fluid Detection of rabies antibodies in cerebrospinal fluid is generally
considered diagnostic, but may not be detected in all cases.

Antigen Brain The most sensitive test for the confirmation of rabies virus infection remains 11
the post-mortem detection of rabies virus nucleocapsid protein in brain
detection assay tissue.

Skin biopsy The detection of rabies virus antigen deposited in the nerve endings 15
at the base of hair follicles in skin biopsies presents a sensitive assay for
confirmation of infection. Specialised equipment required to perform the
test and may not be available from all laboratories.

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costs, improve access and to be dose-sparing, but still vaccine,17 a response that requires 7-10 days. Several Treatment approaches
to maintain efficacy.2 The South African guidelines have rabies immunoglobulin (RIG) products are available in
been revised accordingly and are based on the best South Africa (see Table 5b).
scientific evidence that guided the WHO recommen-
dations. The WHO categorises exposures in three groups To be effective, as much as possible of the immu-
(no risk to absolute risk), based on a risk assessment of noglobulin must be infiltrated directly into the wound.2
the exposure event, with PEP responses dictated by the All wounds must be infiltrated and the immunoglobu-
category of exposure.2 The requirement of PEP must be lin may be diluted if multiple wounds are present. There
assessed case by case, and is based primarily on the like- would seem to be very limited value of RIG injected
lihood of rabies in the animal (see Figure 1 and Table 4).2 intramuscularly, as was recommended in the previous
guidelines2. The use of local anaesthetic agents to fa-
In South Africa, two purified cell-culture vaccines are cilitate the administration of immunoglobulin is discour-
available for use (see Table 5a). These vaccines are aged and suturing of wounds should be delayed where
considered safe for use in all groups. In a patient with possible to reduce the potential for virus spread.2
severe egg-protein allergy, the use of the vaccine pre-
pared in chick embryo could be reconsidered. These Category 3 exposures (i.e. exposure that involved any
vaccines are delivered intramuscularly (but never into breach of the skin) from animal bites are common and
the gluteus muscle), using the modified 4-dose Essen do not necessarily imply a rabies risk implicitly if the in-
schedule (days 0, 1, 7, 14).2 The intradermal (ID) route cident is related to expected animal behaviour, e.g. a
of rabies-vaccine administration is also recommended dog bite from a provoked attack. Indiscriminate use of
as a route of administration and ID regimens present rabies PEP is discouraged due to the limited supply of
the preferred protocol for rabies vaccine administration biologicals and the exorbitant cost of the treatment.
in many countries.2 This is a cost- and dose-sparing ap- Post-exposure prophylaxis failures have been ascribed
proach if multiple doses can be drawn from one vial to deviation from recommended PEP protocols, omit-
over <6-8 hours, a situation which is only feasible in high ting rabies immunoglobulin when it was indicated, and
throughput rabies-prevention clinics, and where staff in rare cases of very severe exposure, particularly when
are well trained in the administration of intradermal involving the head, shoulders or highly innervated areas
vaccinations. If an open vial is kept for a longer period, (such as fingers).18
contamination of the vial is a major risk. In South Africa,
the ID route of administration is only currently recom- Unusual exposures
mended when larger groups of patients receive pre-ex-
posure prophylaxis (PrePEP) simultaneously (e.g. groups Bats
of travellers, or groups of persons requiring vaccination
for protection against work-related exposures).2 In South Africa, classic rabies is not associated with bats,
as is the case in the Americas. It must, however, be
Thorough wound lavage is a critical component of noted that the Duvenhage virus, which has been asso-
management and facilitates physical virus removal. Ra- ciated with several human rabies cases, and Lagos bat
bies immunoglobulin is important to infer passive immu- virus have been reported from South Africa.6-7 Bat ex-
nity, while the body is mounting antibodies against the posures may be quite subtle and difficult to assess.2 It is
recommended that all bat exposures are regarded as
category 3 exposures for this reason.

Patient exposed to potential rabid animal

No PEP NO YES Was the animal a small rodent, such as
required a squirrel, mouse, hamster or rat?
Was the animal a mammal?

NO YES

No PEP NO Was the animal a dog, cat, domestic livestock No PEP
required (i.e. cattle) or bat? Did the animal display required

Institute PEP in unusual behaviour? If domestic, was the animal
accordance
with national stray or unknown to the patient? Did it display

guidelines any signs or symptoms of rabies? Was the

Continue and YES attack unprovoked?
complete PEP
NO Animal available for assessment? Continue and
according complete PEP
to national NO
guideline according
to national
Discontinue PEP guideline

Animal tests negative for rabies, or shows no signs or YES

YES symptoms of rabies after 10 days of observation

Figure 1. Decision tree to aid in management decisions for suspected rabies exposures. (* See Table 1 for animals
confirmed with rabies virus infection in South Africa.)

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154 TREATMENT APPROACHES

Table 4. Post-exposure prevention of rabies in humans

Prevention of rabies in humans

Rabies exposure risk assessment
• A risk assessment is essential to determine if the animal exposure carries a risk of rabies transmission and therefore
whether rabies post-exposure prophylaxis (PEP) is necessary
• This assessment is based on geographical area, animal species, the behaviour of the animal, and the health of the
animal
• Indicators of high-risk rabies incidence include:
o Unprovoked animal attack: Please note: Teasing an animal, trying to take an animal’s food or a guard dog
attacking an unfamiliar person entering their territory, are provoked attacks
o An animal with abnormal behaviour – e.g. domestic animals being unusually aggressive without being provoked;
wild animals appearing “tame”.
o Animal appearing sick – drooling, wobbling/unsteady gait, snapping at imaginary objects
o Animal having died soon after the human attack or within two weeks of the human attack
• If the incident suggests any of the above, then give rabies PEP if the category of exposure is 2 or 1 – see below

Notes All animal bites are reportable as per district requirements
• There is NO blood test to confirm or exclude rabies virus transmission from animal to human at the time of exposure
• The vaccination history of an animal may be unreliable, and as such, should be treated with caution and be given
• least weight in the risk assessment
Do not delay PEP pending test results for the animal
• If the responsible veterinarian later confirms the animal is rabies- free, then PEP can be discontinued
• PEP is most effective if given immediately after the exposure
• Do not withhold PEP when there is a delay in the patient presenting to a health facility
• If PEP is given, Day 0 is the date the first rabies vaccine dose is given
•

Management of patients exposed to potentially rabid animal

General wound management is critical in all patients:
• Flush very well with soap and water or water alone if soap is not available, for 5-10 minutes, then clean with 70% alcohol
solution
• After cleaning, apply iodine solution or ointment if available
• Give antibiotics, e.g. amoxicillin clavulanate, when indicated
• Give tetanus vaccination or booster. Avoid suturing, compressing wound and use of local anaesthetic agents, if
possible

Further specific management depends on the category of rabies exposure and previous vaccination history:
• Vaccine course in category 2 and 1 exposure*
• Addition of rabies immunoglobulin in category 1 exposures is critical**
• If a patient has had three or more rabies vaccines in the past, then give two booster doses on days 0 and 1 post
exposure

Categories of exposure

Category Description Action

1 • Touching or feeding the animal • No action if the history of exposure is reliable
• Licking intact skin • If the history of exposure is not reliable, treat as

category 2

2 • Nibbling of uncovered skin • General wound management as above, plus

• Superficial scratch without any bleeding • Give a full course of rabies vaccine*

3 • Bites or scratches penetrating skin or • General wound management as above, plus

drawing even a drop of blood • Give a full course of vaccine*

• Licking of mucous membranes, such as • Give rabies immunoglobulin**

eyes and mouth • Administration of rabies immunoglobulin is critical in

• Licking of broken skin or abrasions category 1 bites

• Bat exposures (most bites are felt, but not

seen)

Rats, mice, squirrels and other small mammals Monkeys and baboons
Rabies is rarely reported in smaller mammals, such as Rabies is rarely reported in monkeys and baboons. Mon-
rats, mice, gerbils and squirrels (see Table 1). These ani- keys, in particular, are easily provoked to bite. Rare cas-
mals are easily frightened and commonly bite. They es have been associated with captive animals.
would likely be killed when exposed to rabid animals
and not survive to develop and subsequently transmit Special considerations
rabies. Special consideration should be given to the
history of the exposure and unprovoked attacks asso- Immunocompromised individuals
ciated with feral animals should be considered as a
risk. Individuals with documented immunodeficiency, such
as symptomatic HIV infection, should be evaluated on
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Table 5a. Rabies vaccines licensed for use in humans in South Africa Treatment approaches

Product name Dosage Site of administration Schedule

i. Verorab™ 0.5 ml (one vial) Intramuscular. A deltoid muscle in One dose each on days **0, 1, 7 and
ii. Rabipor™ 1.0 ml (one vial) adults, anterolateral thigh in small any day between day 14 and 28
children (aged <2 years)*

* The dosing for both adults and children is the same.
**Day 0 is the day of presentation to a health facility

Table 5b. Rabies immunoglobulin products available in South Africa

Product name Maximum Description Site of administration Schedule
i. Rabigam® dosage
20 IU/kg body 150 IU/ml Infiltrate up to the maximum On day 0 (when a patient
ii. KamRAB® weight Supplied in a calculated dose in and around the presents for the first time)/ASAP
2 ml vial wound site/s. after exposure to be effective to
20 IU/kg body For smaller wounds/areas where it neutralise the virus. When RIG is
weight 150 IU/ml is not possible to infiltrate all of the not available, it should be sourced
Supplied in 2, 5 calculated doses, infiltrate as much as a matter of urgency. When
and 10 ml vials. as is anatomically feasible in and 7 days have lapsed since initial
around the wound site/s. rabies vaccination, RIG is no longer
indicated.
iii. Equirab® 40 IU/kg body 200 IU/ml Infiltrate up to the maximum
weight Supplied in a calculated dose in and around the On day 0 (when the patient
5 ml vial. wound site/s. presents for the first time)/ASAP
For smaller wounds/areas where it after exposure to be effective to
is not possible to infiltrate all of the neutralise the virus. When RIG is
calculated doses, infiltrate as much not available, it should be sourced
as is anatomically feasible in and as a matter of urgency. When
around the wound site/s. 7 days have lapsed since initial
rabies vaccination, RIG is no longer
indicated.

a case-by-case basis and receive a complete course the virus and may be life-saving. When patients present
of PEP, including RIG (see Tables 5a and b).2 Irrespec- after the exposure event, regard the first day of pres-
tive of the category of exposure or previous vaccination entation as day 0 for vaccine and RIG administration.
history, RIG and four doses of rabies vaccine should be If wounds have healed, the RIG should still be infiltrated
administered, one on each day of days 0, 1, 7 and any in and around the wound site. No doubling of doses or
day between day 14 and 28. change to the prescribed regimen is recommended.
Do not administer RIG 7 days after administering the
Pregnant and lactating women first vaccine dose; the vaccine will be effective at this
Rabies vaccine and RIG are safe and effective in preg- stage, and the use of RIG will provide no advantage in
nant and lactating women and should be given if indi- terms of prevention.
cated.2 The dose is the same as in a non-pregnant adult
(see Tables 5a and b). Pre-exposure prophylaxis

Patients who have received previous PrEP or PEP Persons with increased occupational risk of exposure to
In these individuals, RIG is not indicated. For PEP, admin- infection, such as veterinary staff, wildlife handlers, labo-
ister two doses of rabies vaccine on days 0 and 1 to ratory personnel working with rabies virus or animal wel-
boost immunity from previous immunisation. Rabies vac- fare staff, should receive rabies PrePEP.2 Rabies is also
cination provides long-lasting immunity. In the event of an important disease for the travelling community.2,19
repeat exposures (i.e. re-exposure within one month of Dog-associated rabies is endemic in many developing
completion of PEP), rabies PEP is not recommended in countries of Asia, Africa and South America. This poses a
individuals with a previous history of rabies pre-exposure particular threat in the backpacking or adventure-travel
prophylaxis (PrEP) or PEP. For repeat exposures occur- category. Consider pre-exposure rabies vaccination as
ring >1 month after the last PEP, the PEP schedule for this obviates the need for post-exposure RIG, a commod-
previously immunised individuals should be followed; ity that is often unavailable in many settings. The updated
two doses of rabies vaccine should be administered on 2018 WHO guidelines recommend two doses of vaccine
days 0 and 1. into the deltoid muscle on days 0 and 7.2 Administration
of vaccine using the intradermal route provides an effec-
Delayed presentation tive alternative strategy that is cost- and dose-sparing,
Rabies PEP should ideally be provided as soon after ex- provided multiple persons can be immunised at the same
posure as possible as it acts immediately to neutralise time. The schedule requires 0.1 ml of vaccine adminis-
tered intradermally in both deltoid areas on day 0 and
repeated on day 7. Current data show that this regimen

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156 TREATMENT APPROACHES

will elicit protective immune responses up to four years 6. Swanepoel R. Rabies. In: Coetzer JAW, Tustin RC, editors. Infectious
after immunisation and respond to boosting.2 It is likely diseases of livestock: With special reference to southern Africa.
that this period will be longer, but additional data are Cape Town: Oxford University Press; 2004:1121-1184.
awaited. In the interim, consideration should be given to
the three-dose schedule (days 0, 7 and 21 or 28) in cases 7. Weyer J, Szmyd-Potapczuk AV, Blumberg LH, et al. Epidemiology
where the person would be at high or continual risk of ex- of human rabies in South Africa, 1981-2007. Virus Research. 2011;
posure and have limited or no access to rabies antibody 155(1):281-290.
testing and/or booster rabies vaccination.
8. Sabeta CT, Weyer J, Geertsma P, et al. Emergence of rabies in the
Give two booster doses of vaccine to persons who Gauteng Province, South Africa: 2010-2011. Journal of the South Afri-
have received pre-exposure vaccination if there is ex- can Veterinary Association. 2011;84(1): doi:10.4102/jsava.v84i1.921.
posure to a suspected rabid animal, regardless of the
rabies serum antibody level of the patient. These are 9. Le Roux K, Stewart D, Perrett KD, et al. Rabies control in KwaZulu-
given on days 0 and 3.2 Importantly, RIG should be omit- Natal, South Africa. Bulletin of the World Health Organization.
ted post-exposure since it may depress the rapid boost- 2018;96(5):160.
ing of antibodies. It is not clear how often this group
of people with ongoing potential exposure should be 10. Johnson N, Fooks A, McColl K. Re-examination of human rabies
given boosters; some authorities recommend boosters case with long incubation, Australia. EID. 2008;14(12):1950-1951.
every one to five years. Measurement of serum anti-
body levels may guide the process. 11. Hemachundha T, Ugolini G, Wacharapluesadee S, et al. Human
rabies; neuropathogenesis, diagnosis, and management. Lancet
Treatment of suspected rabies patients Neurol. 2011;12:498-511.

Rabies is regarded as the most deadly infection known 12. Hemachunda T, Laothamatas J, Rupprecht CE. Human rabies: A
to mankind and is almost invariably fatal in all cases. disease of complex neuropathogenetic mechanisms and diag-
Few cases of survival have been noted in patients with nostic challenges. Lancet Neurol. 2002;1:101-109.
a history of pre-exposure vaccination. A single case of
survival with a favourable neurological outcome was 13. Jackson AC. Current and future approaches to the therapy of hu-
reported in a teenage girl in the United States in 2004.20 man rabies. Antiviral Research. 2013;99(1)61-67.
The patient was exposed to a rabid bat and did not re-
ceive any post-exposure prophylaxis. Once rabies was 14. Blumberg L, Weyer J, Frean J, Ogunbanjo GA. Rabies: An evidence-
considered the likely diagnosis, an experimental treat- based approach to management. SA Fam Pract. 2007;49(5):16-19.
ment protocol was employed, which may be described
as induction of non-excitatory coma and treatment 15 Dacheux L, Reynes JM, Buchy P, et al. A reliable diagnosis of human
with an antiviral cocktail.20 Updates of this treatment rabies based on analysis of skin biopsy specimens. Clin Infect Dis.
protocol are available online (http://www.chw.org/dis- 2008:47:1410-1417.
play/PPF/DocID/33223/router.asp), and several cases
have been treated according to the protocol since the 16. Lembo T, Niezgoda M, Velasco-Villa A, et al. Evaluation of a di-
original case, but without the same outcome.21 The pa- rect, rapid immunohistochemical test for rabies diagnosis. EID.
tient had an unusually high natural antibody response 2006;12(2):110-111.
early during the disease in the absence of passive or ac-
tive immunisation against rabies. Research is ongoing to 17. Both L, Banyard AC, von Dolleweerd C, et al. Passive immunity in
elucidate the mode of survival, but host factors (i.e. the the prevention of rabies. Lancet. 2012;12:197-407.
patient’s own immune response) and viral factors (de-
creased neurovirulence of bat-derived rabies virus) are 18. Wilde H. Failures of post-exposure rabies prophylaxis. Vaccine.
implicated.13 Typically, patients are treated empirically. 2007;25(44):7605-7609.
The focus should be on settling the patient as comfort-
ably as possible and consoling the family members. 19. World Health Organization. 2012. Vaccine preventable disease
and vaccines. In: International Travel and Health. Available from:
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March 2019.)
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April 2018. Available from: http://apps.who.int/iris/bitstream/han- 21. Zeiler FA, Jackson AC. Critical appraisal of the Milwaukee protocol
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Journal of Neurological Sciences. 2016;41(1):44-51.
3. International Committee on the Taxonomy of Viruses. Lyssaviruses.
The 10th Report of the ICTV. Available from: https://talk.ictvonline.
org/ictv-reports/ictv_online_report/negative-sense-rna-viruses/
mononegavirales/w/rhabdoviridae/795/genus-lyssavirus (access­ ed
7 January 2019).

4. Rupprecht CE, Turmelle A, Kuzmin IV. A perspective on lyssavirus
emergence and perpetuation. Current Opinion in Virology. 2011;
1:662-670.

5. Johnson N, Vos A, Freuling C, et al. Human rabies due to lyssavirus
infection of bat origin. Veterinary Microbiology. 2010; 142:151-159.

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Tuberculosis IRIS Treatment approaches

JS Nel commonly has a prominent role for immune-mediated
damage, rather than direct pathogen-associated dam-
MBChB, FCP(SA), DTM&H age, which may partially explain their association with
IRIS. Occasionally, non-HIV-related conditions, such as
Division of Infectious Diseases, Department of Medicine, sarcoidosis or Graves' disease, have been similarly un-
Helen Joseph Hospital, Johannesburg; Department masked after starting ART. Also, there are reports of IRIS-
of Medicine, University of the Witwatersrand, Johannesburg like reactions occurring even in the absence of ART initia-
tion, if CD4-related immune function rapidly improves for
Tuberculosis IRIS reasons other than ART. Such scenarios may include the
treatment of tuberculosis itself and can occur in the ab-
Tuberculosis (TB) remains a significant burden in South sence of HIV.6 However, such instances are rare.
Africa and the world in general. In 2017, there were an
estimated 10 million new TB cases worldwide, and 1.6 Risk factors
million deaths from TB.1 Approximately 300 000 of these
deaths were among people living with HIV. Of over Two risk factors have been consistently associated with
220 000 new and relapsed TB cases notified in South Af- the development of IRIS: a low baseline CD4 count at
rica in 2017, roughly 60% were HIV-positive.1 This gives ART initiation, and a high HIV viral load at ART initiation.7
South Africa one of the highest burdens and prevalenc- Similarly, several studies have documented that a rapid
es of TB-HIV co-infection in the world. rate of change in these two parameters is similarly asso-
ciated with a risk of IRIS.8
Among the unique complications that TB-HIV co-
infection brings, is the TB immune reconstitution inflam- Timing
matory syndrome (IRIS). This is an immune-mediated
syndrome where improving immune function, typically IRIS reactions occur a median of two to three weeks af-
seen after starting antiretroviral therapy (ART), causes ter ART is commenced, but the timing is usually some
an increase in the inflammation directed towards the time between one week and three months after ART.9
antigens of Mycobacterium tuberculosis. There are two IRIS reactions occurring later than three months after
forms of TB IRIS. Unmasking TB IRIS occurs where signs ART initiation are uncommon, although they have been
and symptoms of TB develop for the first time in a sub- reported.5
clinically infected patient after initiating ART. Paradoxi-
cal TB IRIS occurs where a patient, already known to Left to themselves, the median duration of TB IRIS re-
have TB, sees a temporary exacerbation of symptoms actions is approximately two months, although a wide
following ART introduction. range of durations is seen, and in many cases, it is shorter.3

In a meta-analysis, the risk of tuberculosis IRIS was just Clinical manifestations
over 15%, but the risk may be substantially higher in pa-
tients with low baseline CD4 counts. Nearly half of TB IRIS In principle, the clinical manifestations of TB IRIS are iden-
cases result in hospitalisation.3,4 However, the mortality tical to those of tuberculosis, though their onset may be
from TB IRIS is estimated at only 3.2%.2 The one exception quicker and occasionally more severe than non-IRIS-as-
to this relatively benign course is the involvement of the sociated TB. The majority of TB IRIS cases involves more
central nervous system (CNS), where mortality may be than one site or organ system. The site of a paradoxical
significantly higher.5 TB IRIS may be quite distinct from the original site of clini-
cally evident tuberculosis – for instance, a patient may
Pathophysiology be treated for pulmonary TB, but present with a TB IRIS
reaction involving a cervical lymph node. Although any
IRIS reactions are thought to be the result of the resto- site can be involved in TB IRIS, the main sites are:
ration of vigorous immune reactivity directed towards - Lymph nodes
antigens of the relevant pathogens. They are gener- - Lungs
ally caused by the introduction of effective ART. Rather - Central nervous system
than being a non-specific phenomenon, IRIS reactions - Abdomen
appear to be most closely associated with a select sub-
group of pathogens, i.e. mycobacterial infections (such Lymphadenitis occurs in ~40% of TB IRIS cases, and
as TB or Mycobacterium avium complex infections), the course of this form of TB IRIS is notoriously prone to
deep fungal infections (such as cryptococcal meningitis be prolonged, often lasting for many months.10 It typi-
or Pneumocystis jirovecii), herpes virus infections (such as cally presents as a painful, inflamed, often markedly en-
CMV or HSV), hepatitis B, JC virus, human papilloma virus- larged lymph node that progresses to suppuration over
associated genital warts, and some AIDS-associated ne- several weeks (see Figure 1).
oplasms (lymphomas and Kaposi sarcoma). The patho-
genesis of many of the infections linked to IRIS reactions Pulmonary involvement in TB IRIS occurs in a similar pro-
portion of cases.10 It can consist of pleural effusions, en-

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158 TREATMENT APPROACHES

Figure 1. A patient with paradoxical TB IRIS involving gamma-glutamyl transferase), rather than the transami-
the cervical lymph nodes nitis than is typical of drug-induced liver injuries.

larging hilar or paratracheal lymphadenopathy, or the TB IRIS manifestations are frequently accompanied by
development of new nodules or worsening infiltrates. fevers, weight loss, night sweats and/or loss of appetite.
Occasionally, these symptoms may be the only mani-
Central nervous system involvement typically takes festation of TB IRIS.11
one of two forms: TB meningitis or intracerebral tuber-
culomas. Interestingly, in one study, patients who later Diagnosis
developed a paradoxical TB meningitis had IRIS with
significantly higher baseline cerebrospinal fluid (CSF), There is no commercially available test for IRIS. Instead,
neutrophil counts and lower CSF glucose levels than identifying the syndrome rests on several key data
those who did not develop TB meningitis IRIS.10 Because points:
of its location, IRIS within the nervous system is far more 1. Signs and symptoms compatible with TB, and in the
likely to result in permanent disability or death than IRIS
elsewhere in the body.5 case of paradoxical TB IRIS, worsening of TB symp-
toms after initial improvement.
Abdominal TB IRIS may result in (or can exacerbate) he- 2. A temporal association with ART – generally within
patomegaly, splenomegaly, abdominal lymphadeno- the first three months – and ideally associated with
pathy or ascites. With hepatic involvement, the typical a significant change in HIV viral load and/or CD4
pattern seen on liver-function tests is that of cholestasis count over that period.
(i.e. disproportionately high alkaline phosphatase and 3. Exclusion of other possible causes of clinical deterio-
ration.
Over the years, several groups of authors have put
together a variety of different case definitions for both
IRIS in general and for TB IRIS specifically. One example
from each group is outlined in Table 1. These definitions
were developed primarily to define groups for research
purposes clearly, but they may also be used for clini-
cal diagnosis. The case definition that is most used in
limited-resource settings is that of Meintjes et al, which
benefits from clear and clinically relevant criteria.9 How-
ever, disadvantages of this case definition include its
limitation to paradoxical TB IRIS cases (rather than un-
masking TB IRIS cases) and the lack of any CD4 or HIV
viral load criteria. The latter may be helpful in the clinical
setting. TB IRIS is extremely unlikely without a substantial
decrease in baseline viral load and/or a substantial in-
crease in CD4+ T cells from baseline (though the latter

Table 1. Examples of case definitions for IRIS in general and for TB IRIS

General case definition for IRIS – Shelburne et al.12 Case definition for paradoxical TB IRIS – Meintjes et al.9

HIV-infected patient TB adequately diagnosed and good initial response to TB treatment

Receiving effective ART as evidenced by a decrease in Onset within 3 months or ART initiation, re-initiation, or regimen change
HIV-1 RNA concentration from baseline or an increase in because of treatment failure
CD4+ T cells from baseline

Clinical symptoms consistent with the inflammatory One major clinical criterion or two minor clinical criteria:
process Major criteria:

• New or enlarging lymph nodes, cold abscesses, or focal tissue
involvement

• New or worsening radiological features of TB
• New or worsening CNS TB
• New or worsening serositis

Minor criteria:
• New or worsening constitutional symptoms
• New or worsening respiratory symptoms
• New or worsening abdominal pain accompanied by peritonitis,

hepatomegaly, splenomegaly or abdominal adenopathy.

Clinical course not consistent with the expected course Alternative explanations for clinical deterioration must be excluded, if

of previously diagnosed opportunistic infection, expect- possible:

ed course of newly diagnosed opportunistic infection, or • TB drug resistance

drug toxicity • Poor adherence to TB treatment

• Another opportunistic infection or neoplasm

• Drug toxicity or reaction

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Table 2. Selected mimickers of TB IRIS syndromes Treatment approaches

Syndrome Common mimickers Suggested basic screening

Pulmonary infiltrates or pleural effusion Bacterial pneumonia Sputum culture
PCP Serum beta-D-glucan
Kaposi sarcoma Thorough skin and oral exam
Cryptococcal lung disease Serum CrAg

CNS ring-enhancing lesion Toxoplasmosis Toxoplasma serology
Cryptococcoma Serum and/or CSF CrAg
Primary CNS lymphoma CSF EBV viral load

Lymphadenopathy Lymphoma Lymph-node biopsy
Carcinoma

Hepatosplenomegaly and abdominal Lymphoma Biopsy of any amenable nodes
lymphadenopathy MAC Mycobacterial blood culture
Cryptococcosis Serum CrAg
Nontyphoidal salmonellosis Bacterial blood cultures

PCP – Pneumocystis jirovecii pneumonia, CNS – central nervous system, MAC – Mycobacterium avium complex, CSF – cerebrospinal fluid,
CrAg – cryptococcal antigen test, EBV – Epstein-Barr virus

may sometimes lag behind the HIV viral load change). Third, corticosteroids can be given to decrease the
Consequently, these lab criteria can assist clinicians in symptom severity of TB IRIS. Since TB IRIS is self-limiting,
cases of diagnostic uncertainty and should be incorpo- mild cases do not necessarily require corticosteroids.
rated where possible. However, cases of TB IRIS associated with significant dis-
comfort or morbidity should generally receive cortico-
Critical to the diagonisis of TB IRIS is the exclusion of steroids. A randomised control trial showed that a four-
other possible causes of clinical deterioration. Table 2 week regimen of prednisone significantly decreased a
describes common mimickers of various TB IRIS syn- composite end-point consisting of days of hospitalisation
dromes, along with quick methods to screen for these. and outpatient therapeutic procedures.4 Improvements
It is also important to realise that patients may be co- in self-reported symptoms, Karnofsky performance score,
infected with multiple pathogens, and in a patient with quality of life score, C-reactive protein and chest radi-
TB who initially improves and then deteriorates after ography score were also significantly higher in the pred-
commencing ART, what appears to be a paradoxical nisone group, compared to the placebo group within
TB IRIS may, in fact, be an unmasking IRIS for a separate the first four weeks – but not afterwards. Despite the sig-
pathogen. nificant symptomatic improvement, there was no mortal-
ity benefit in this trial, principally because of the low base-
Treatment line mortality rate from TB IRIS in general. If prednisone
is given for TB IRIS, it is important to note that rifampicin
There are three components in managing a case of TB IRIS: induces the metabolism of prednisone, and so doses of
First, antituberculous treatment should be continued prednisone should account for this. The prednisone regi-
men used in the above trial is outlined in Table 3.
wherever possible. This includes cases of mild- to mode-
rate liver dysfunction that sometimes accompanies Table 3. Suggested prednisone regimen for the
systemic or abdominal IRIS reactions. In cases of signifi- treatment of TB IRIS
cant liver dysfunction (conventionally defined as biliru-
bin >40 µmol/L or ALT >200 IU/L), antituberculous drug Prednisone 1.5 mg/kg daily for two weeks, followed by
therapy may have to be altered to a less hepatoxic Prednisone 0.75 mg/kg daily for two weeks
regimen.13 However, this comes at the cost of providing
less effective TB therapy, and so the risks and benefits of Prednisone therapy is not without potential down-
this approach need to be weighed up carefully. Con- sides, and in some patients, the risks will outweigh the
sultation with an infectious diseases specialist is recom- benefits. These include patients with Kaposi sarcoma
mended in this scenario. (in whom corticosteroids are contra-indicated), most
patients with diabetes mellitus, and some patients with
Second, antiretroviral therapy should also usually be hepatitis  B, in whom the disease may flare with high-
continued wherever possible. TB IRIS carries a low over- dose corticosteroids. Before commencing prednisone,
all mortality rate, and the risks of interrupting ART, such make a careful assessment of each patient to exclude
as developing drug resistance to ART, comfortably out- these and other conditions that may influence the risk-
weigh the benefits in most scenarios. An exception to benefit calculation.
this is where the patient has a truly life-threatening IRIS.
This applies mainly to TB IRIS within the CNS. In these Prevention
cases, it may sometimes be prudent to withhold ART for
a period in order to assist in reducing the inflammatory In 2018, results of a randomised control trial were pub-
response that ART has helped to generate. Again, con- lished that compared prophylactic prednisone to pla-
sultation with an infectious diseases specialist is strongly cebo in HIV-positive patients with a CD4 count under
recommended in cases where interruption of ART is
contemplated. HANDBOOK OF GENERAL MEDICINE VOL 1

160 TREATMENT APPROACHES

100 cells/mm3 who were initiating ART less than a month 13. Jong E, et al. Consensus statement: Management of drug-induced
after having commenced TB treatment.14 The aim was liver injury in HIV-positive patients treated for TB. Available at: htt-
to evaluate prednisone for the prevention (rather than ps://sahivsoc.org/Files/Consensus%20Statement_Management%20
treatment) of TB IRIS. Those in the treatment arm re- of%20drug-induced%20liver%20injury%20in%20HIV%20positive%20
ceived 40 mg prednisone per day for two weeks, fol- pts%20treated%20for%20TB%20(Oct%202013).pdf. Accessed Janu-
lowed by 20 mg per day for two weeks (see Table 4). ary 2019.
Forty-seven percent of the placebo group developed
TB IRIS, compared with 33% of the prednisone group. This 14. Meintjes G, et al. Prednisone for the prevention of paradoxical tu-
translates into a 30% relative risk reduction for the pred- berculosis-associated IRIS. NEJM 2018; 379:1915-25
nisone group or the prevention of one case of TB IRIS
for every seven patients treated with prednisone. Again,
despite this, no effect on mortality was seen. There was
no significant difference in rates of serious infection or
neoplasm between the two groups. It must be noted
that important subgroups of patients were excluded in
this trial – amongst others, patients with hepatitis B co-
infection, those with pericardial or rifampicin-resistant
TB, those on non-standard TB regimens, those with Ka-
posi sarcoma and those with uncontrolled diabetes.
Also, only adults were enrolled. Thus, the extrapolation
of these generalised results to routine clinical practice
may be somewhat limited. Nonetheless, the trial does
suggest that prednisone may safely prevent TB IRIS in
many HIV patients commencing ART, provided the pa-
tient has been carefully evaluated for any contra-indi-
cating conditions beforehand.

Table 4. Suggested prednisone regimen for the
prophylaxis of paradoxical TB IRIS in adults

Prednisone 40 mg/day for two weeks, followed by

Prednisone 20 mg/day for two weeks

References

1. World Health Organization. Global Tuberculosis Report 2018. Avail-
able at: https://www.who.int/tb/publications/global_report/en/
Accessed January 2019.

2. Müller M, et al. Immune reconstitution inflammatory syndrome in
patients starting antiretroviral therapy for HIV infection: A systematic
review and meta-analysis. Lancet Infect Dis. 2010;10:251-61

3. Burman W, et al. Frequency, severity and duration of immune re-
constitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis.
2007;11(12):1282-9

4. Meintjes G, et al. Randomized placebo-controlled trial of pred-
nisone for paradoxical tuberculosis-associated immune reconstitu-
tion inflammatory syndrome. AIDS. 2010;24:2381-2390

5. Agarwal U, et al. Tuberculosis-associated immune reconstitution in-
flammatory syndrome in patients infected with HIV: Meningitis a po-
tentially life-threatening manifestation. AIDS Research and Therapy.
2012;9(17)

6. Geri G, et al. Paradoxical reactions during treatment of tuberculosis
with extrapulmonary manifestations in HIV-negative patients. Infec-
tion. 2013; 41:537-543

7. Grant PM, et al. Risk factor analyses for immune reconstitution syn-
drome in a randomized study of early vs deferred ART during an
opportunistic infection. PLoS One. 2010;5(7):e11416. Epub 2010 Jul 1.

8. French MA, et al. Immune restoration disease after the treatment of
immunodeficient HIV-infected patients with highly active antiretro-
viral therapy. HIV Med. 2000; 1(2):107

9. Meintjes G, et al. Tuberculosis-associated immune reconstitution in-
flammatory syndrome: Case definitions for use in resource-limited
settings. Lancet Infect Dis. 2008; 8:516-23

10. Bana T, et al. Prolonged tuberculosis-associated immune reconsti-
tution inflammatory syndrome: Characteristics and risk factors. BMC
Infect Dis. 2016;16:518

11. Marais S, et al. Frequency, severity, and prediction of tuberculous
meningitis immune reconstitution inflammatory syndrome. Clin In-
fect Dis. 2013; 56(3):450-60.

12. Shelburne SA, Montes M, Hammill RJ. Immune reconstitution inflam-
matory syndrome: More answers, more questions. J Antimicrob
Chemother. 2006;57:167-70

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Fibromyalgia: diagnosis and management Treatment approaches

B Hodkinson ble bowel syndrome, dysuria, nausea, dizziness, para-
esthesia and numbness, transient rashes and alopecia
MBBCh, PhD, FCP (SA), Cert Rheum (see Figure 2).

Professor and Head, Rheumatology Division, Department dyPshfuynsicctaiol n Sleep
of Medicine, University of Cape Town and Groote Schuur disturbances
Hospital, Cape Town
Mutiple PAIN Sexual
Fibromyalgia syndrome is a chronic condition asso- chemical dysfunction
ciated with widespread pain, fatigue and tender sensitivity
points. Fibromyalgia patients also commonly present
with a range of other problems, including dysregulated Dyscognition Fatigue
sleep, cognitive dysfunction, functional bowel disorder,
paraesthesias and mood disturbance. The condition af- Mood Physical Anxiety/
fects women more often than men, and the incidence disturbances dysfunction psychological
increases with age, with the peak onset in midlife. Glob-
ally, fibromyalgia affects 3-5% of the population, and in distress
the primary care setting, up to one in 20 patients has
symptoms of fibromyalgia.1 Tenderness Overlapping
to touch conditions
Pain in fibromyalgia often varies in location and inten-
sity and often has neuropathic-like qualities (i.e. burning Figure 2. Symptoms of fibromyalgia may include pain,
pain). This pain in fibromyalgia is frequently aggravated fatigue, sleep and mood disturbance and a variety
by poor sleep, emotional disturbances and weather of somatic symptoms
changes.
Pathogenesis
Another critical symptom in fibromyalgia is fatigue,
and it has physical (lack of energy), emotional (lack The cause of fibromyalgia is not known, but an under-
of motivation), cognitive (inability to concentrate) as- lying genetic predisposition (first-degree relatives of
pects, frequently with a negative impact on the ability patients with fibromyalgia have an eightfold increased
to work, meet family needs, or engage in social activi- likelihood of developing fibromyalgia) and triggering
ties.2 Fatigue in fibromyalgia, sometimes described by event/s of mental or physical trauma, including medi-
sufferers as extreme jet lag, is complex and interrelated cal illness, seem to play a role. The most substantial
with other fibromyalgia symptoms, the presence of co- evidence points to dysregulation of pain modulation
morbidities, and therapies offered for symptom control in the central nervous system, with an increased neural
(see Figure 1). response to pain and attenuated inhibitory process of
noxious stimuli. There is also some evidence that there
is dysregulation of stress responses in the sympa­tho-
adrenal and hypothalamic-pituitary-adrenal systems.

Unrefreshing Autonomic Diagnosis
sleep symptoms
The American College of Rheumatology (ACR) pub-
Depressed Cognitive Fatigue lished diagnostic criteria for fibromyalgia in 1990, based
mood difficulties on chronic (≥3 months), widespread pain involving more
than three sites, with 11 of 18 tender points present (see
Pain Figure 3).3 These points are painful under mild, firm pres-
sure (the equivalent of 4 kg, or such that the examiner’s
Anxiety nail blanches white).

Medical More recently, in an attempt to simplify the diagnosis
comorbidities and recognise the importance of the many non-pain
symptoms of fibromyalgia syndrome, such as perceived
Figure 1. Fatigue and interconnecting symptoms cognitive impairment (“fibrofog”), fatigue, and sleep
in fibromyalgia patients2 disturbance, in making the diagnosis, new criteria have
been developed. A widespread pain index (WPI) and
Somatic symptoms of fibromyalgia include cognitive the symptom severity (SS) scale are required, and fibro-
and sexual dysfunction, headache, weakness, irrita- myalgia is no longer considered a diagnosis of exclusion
(see Figure 4).4 In practice, many clinicians find the new
criteria cumbersome and use the tender point count in
the presence of widespread pain.

The heterogeneity and non-specific nature of fibro-

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162 TREATMENT APPROACHES

DAVE KLEMM myalgia symptoms, the absence of any clinical or labo-
ratory abnormalities and lack of a diagnostic test, and
Figure 3. Tender points for the diagnosis of the concern of overlooking a more severe illness, lead
fibromyalgia. According to the 1990 American many clinicians to the misconception that the diag-
College of Rheumatology Classification Criteria, nosis of fibromyalgia is challenging. Patients frequently
11 of 18 tender points must be present in the setting undergo multiple consultations and exhaustive inves-
of chronic (>3 months) widespread pain tigations before receiving a diagnosis of fibromyalgia.
One study has shown that the diagnosis of fibromyalgia
might take more than two years, with patients seeing
an average of 3.7 different clinicians during this time.5
This diagnostic delay, together with common miscon-
ceptions regarding the legitimacy of the condition, can
have a significant negative impact on patients’ emo-
tional state and quality of life, as well as on societal and
healthcare costs.

Differential diagnosis
and investigations

Fibromyalgia syndrome presents with particular symptoms
and is an easy diagnosis to make. Table 1 lists relevant
differential diagnoses and the investigations the clinician
might consider in the clinical context of each patient.6

Fibromyalgia is one of many related disorders, includ-

Figure 4. The modified 2016 fibromyalgia criteria

A patient satisfies modified 2016 fibromyalgia criteria if the following 3 conditions are met:
(1) Widespread pain index (WPI) >7 and symptom severity scale (SSS) score >5 OR WPI of 4-6 and SSS score >9.
(2) Generalised pain, defined as pain in at least 4 of 5 regions, must be present. Jaw, chest and abdominal pain are not

included in generalised pain definition.
(3) Symptoms have been generally present for at least 3 months.
(4) A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the

presence of other clinically important illnesses.

Ascertainment
(1) WPI: Note the number of areas in which the patient has had pain over the last week. In how many areas has the patient had

pain? Score will be between 0 and 19

Left upper region (Region 1) Right upper region (Region 2) Axial region (Region 5)
Jaw, left Jaw, right Neck
Shoulder girdle, left Shoulder girdle, right Upper back
Upper arm, left Upper arm, right Lower back
Lower arm, left Lower arm, right Chest
Abdomen

Left lower region (Region 3) Right lower region (Region 4)
Hip (buttock, trochanter), left Hip (buttock, trochanter), right
Upper leg, left Upper leg, right
Lower leg, left Lower leg, right

(2) Symptom severity scale (SSS)

Fatigue
Waking unrefreshed
Cognitive symptoms
For each of the 3 symptoms above, indicate the level of severity over the past week using the following scale:
0 = No problem
1 = Slight or mild problems, generally mild or intermittent
2 = Moderate, considerable problems, often present and/or at a moderate level
3 = Severe: pervasive, continuous, life-disturbing problems
The symptom severity scale (SSS) score: is the sum of the severity scores of the 3 symptoms (fatigue, waking unrefreshed, and
cognitive symptoms) (0-9) plus the sum (0-3) of the number of the following symptoms the patient has been bothered by that
occurred during the previous 6 months:
(1) Headaches (0-1)
(2) Pain or cramps in lower abdomen (0-1)
(3) And depression (0-1)

The final symptom severity score is between 0 and 12
The fibromyalgia severity (FS) scale is the sum of the WPI and SSS

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TREATMENT APPROACHES 163

ing chronic fatigue syndrome, multiple chemical sensi- HIV infection (21% of HIV-positive patients) and multi- Treatment approaches
tivity and Gulf War illness, which may present with similar ple sclerosis (14%). Frequently, successful treatment of
symptomatology. Several studies have demonstrated comorbidities improves overall fibromyalgia symptoms.
that these conditions commonly present simultaneous- Some, but not all studies, demonstrated that low vitamin
ly in the same patient and that individuals with one of D levels are commonly seen in fibromyalgia. However,
these conditions are far more likely to have or develop very few studies have assessed the benefit of vitamin D
another of these conditions.7 supplementation in vitamin D-deficient fibromyalgia pa-
tients, with some showing improvement but others show-
Comorbidities ing no benefit.8 Routine vitamin D supplementation for all
fibromyalgia patients is not currently recommended.
Patients with fibromyalgia frequently have comorbid ill-
nesses which may precipitate the fibromyalgia, cloud Treatment
the diagnosis, amplify the disability and complicate the
management. These include chronic rheumatological Fibromyalgia continues to be a challenging condition to
conditions (20-30% of RA, SLE and spondyloarthropathy treat successfully. A lack of an explicit treatment path-
patients), psychiatric disorders (depression, generalised way often results in patients being referred from special-
anxiety disorder, post-traumatic stress disorder, and so- ist to specialist, prescription of multiple drugs to treat
matisation frequently co-exist with fibromyalgia), cardiac different symptoms, and frustration on the part of clini-
disorders, sleep disturbances, irritable bowel syndrome, cians and their patients. Surveys of fibromyalgia patients
chronic fatigue syndrome, interstitial cystitis, headache report dissatisfaction with fibromyalgia medication and
and migraine, hypertension, obesity and dyslipidaemia, overall treatment.5 Unfortunately, few treatment modal-

Table 1. Mimics of fibromyalgia syndrome

System Example History Examination Investigation to consider
Inflammatory arthritis
• Rheumatoid arthritis • Clear onset, • Joint swelling • ESR or CRP
Inflammatory conditions (RA) • Morning stiffness >1 hr
• Pain in joints, entheses • Reduced range of • ANA
Myofascial pain • Psoriatic arthritis • Nocturnal discomfort
syndrome • Systemic lupus • Rash motion of joints (RA) or • Rheumatoid factor
• Raynaulds
erythematosus (SLE) spine (SpA) • X rays, joint sonar
• Spondyloarthropathy
• Rashes, alopecia
(SpA)
(SLE, PSA)
• Polymyalgia
rheumatic • Weight loss • Reduced shoulder • ESR
• Morning stiffness
• Giant cell arteritis • Age >65yrs range of motion • Urine analysis
• ANCA-associated • Jaw claudication,
• Temporal tenderness • ANCA where
vasculitis (AAV) visual changes
• Polyarteritis nodosum • Rash, neuropathy, indicated

(PAM) haematuria (AAV, PAN)

Hypermobility • Benign hypermobility • Regional pain • Trigger points
Endocrine syndrome (eg neck, shoulder,
Gastro-intestinal lower back) • Hypermobile joints
• Ehrers-Danlos • Skin hyperelasticity
Infections syndrome, Marfan • Joint dislocations
Malignancy • Family history
• Hypothyroidism
• Hyperparathyroidism • Weight gain • Proximal myopathy • TSH
• Hypovitamin D • Constipation • Coarse hair • Ca
• Myopathy • Vitamin D level
• Inflammatory bowel
disease • Bloating, diarrhoea • Colonoscopy
• bloody diarrhoea • Transglutaminase
• Coeliac disease
• Irritable bowel antibody

syndrome • Loss of weight • HIV
• Fever • HCV
• Hepatitis C Bone pain FBC,ESR
• HIV Severe pain, especially Investigate as clinically
Carcinoma lympho- at night indicated
or myeloproliferative Loss of weight
myeloma Serum muscle enzymes

Neurological disease • Parkinsons • Tremor, rigidity
• Multiple sclerosis • Gait abnormalities
• Myopathy/myositis • Proximal weakness

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164 TREATMENT APPROACHES

ities show clear statistical benefit in randomised control regimen that they enjoy, and to start with low intensity
trials.9 This may reflect the heterogeneity of fibromyalgia and build up to moderate intensity, maintaining the fre-
patients, the high level of placebo responses amongst quency at two or three times per week.14 Patients’ fears
fibromyalgia patients, and the many overlapping co- of worsening fibromyalgia symptoms when starting ex-
morbidities associated with the condition. As with any ercise should be alleviated. Long-term adherence to
chronic illness with no definitive cure, the responsibility an exercise programme is vital and is related to factors
of the clinician is to stay updated and assess the quality such as self-efficacy and belief in the bene­ fit of the regi-
of evidence for each treatment modality and to pro- men, underscoring the need for education and encour-
tect patients from over-expenditure on unproven rem- agement from healthcare providers.9
edies. Rather than a one-pill-fits-all approach, personal­
ised care plans based on the overall clinical picture of Psychological and behavioural modalities
each patient are needed.10
Research consistently shows that cognitive-behavioural
Non-pharmacological treatment therapy (CBT) is effective in improvi­ng the specific tar-
get variables (such as maladap­tive cognition, mood,
Educa­tion and quality of life), although the effects on the primary
fibromyalgia symptoms, particularly pain, are limited.
Many fibromyalgia patients struggle with social stigma Despite one-on-one sessions being very effective, small
and a search for legitimacy because they often appear group sessions, books, online courses or online groups
healthy, have no visible symptoms, and the syndrome is are less expensive and very useful. CBT is best combined
not well understood by scientists, While being given a with other treatment modalities.
diagnosis may offer an initial sense of relief to patients,
many are disappointed to find that the diagnosis does Improving sleep hygiene through simple steps like pri-
not lead to increased understanding or treatment op- oritising relaxing sleep routines and creating a positive
tions.11 This is where information can play a role. sleep environment can reduce pain and improve men-
tal wellbeing.
Educat­ion is essential to promote self-management and
to enhance the effects of other therapeutic interventions. Pharmacological therapies
Useful aspects of an education session include establish-
ing working goals and shifting the passive patient role Several pharmacological therapies are available to
(“treatment should be given to me”) to an active role. help treat fibromyalgia symptoms (see Table 2).

Exercise Low-dose amitriptyline

Aerobic exercise combined with a strengtheni­ng and Amitriptyline 10-25 mg nocte improves pain (30% im-
stretching programme shows beneficial effects in re- provement in pooled randomised control trials), mild im-
ducing fibromyalgia symptoms and improving physical provement in sleep, but little impact on fatigue. Prescrib-
functioning. Physical deconditioning is common in fibro- ing clinicians should be aware of anticholinergic side
myalgia syndrome and may contribute to the mainte- effects, particularly worsening symptoms of dry eyes and
nance of fibromyalgia.12 Exercise has numerous health dry mouth, urinary retention in elderly patients and those
benefits and may reduce inflammatory and stress re- with prostatism. Notably, higher doses (>25 mg/day) did
sponse in fibromyalgia patients.13 not improve efficacy and increased side effects.

Patients should be encouraged to select an exercise

Table 2. Pharmacological therapies in fibromyalgia

Drug Name Dose Side effects
10-25 mg nocte
Low-dose tricyclic Amityripline 60 mg/d, start at 30 mg/d Dry eyes and mouth,
antidepressant (Trepiline) and increase somnolence, urinary retention

Serotonin- Duloxetine 20 mg daily Nausea, constipation,
noradrenalin re-uptake (Cymbalta) dry mouth, somnolence,
inhibitor 300-450 mg/d start at 75 mg decreased appetite,
BD and increase hyperhidrosis
Serotonin re-uptake inhibitor Fluoxetine 1 200-2 400 mg/day
(Prozac) Insomnia, strange dreams;
50-150 mg dally headache, dizziness, tremor,
Anticonvulsants Pregabalin loss of appetite, nausea,
Opioid (Lyrica) vomiting diarrhoea

Gabapentin Dizziness, somnolence,
(Neurontln) peripheral oedema, and gait
disturbance
Tramadol
Dizziness, somnolence,
peripheral oedema, and gait
disturbance
Somnolence, nausea,
constipation

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TREATMENT APPROACHES 165

Antidepressants Conclusion Treatment approaches
Duloxetine, a serotonin-noradrenalin re-uptake inhibi-
tor, improved pain (30% reduction) with no effect on With a better understanding of the condition and a
sleep or fatigue.15 Higher doses (60 mg/day) are not clear treatment pathway, it is hoped that a diagnosis
more effective. Less expensive antidepressants to con- of fibromyalgia can be promptly and reliably made in
sider are selective serotonin reuptake inhibitors, such as the primary care setting. Multidisciplinary, individualised
fluoxetine, which may improve symptoms, particularly in treatment for fibromyalgia syndrome patients is likely to
depressed patients, although the evidence is low.16 result in the best symptom control, with a stepwise ap-
proach integrating different modalities with periodic as-
Anticonvulsants sessment. A sympathetic primary care physician, who
Pregabalin improved pain (30% reduction) with a small discourages "healthcare practitioner shopping" and ex-
improvement in sleep and fatigue. The significant side pensive, unnecessary investigations or therapies with no
effects are dizziness and drowsiness. Hence, initiation at proven value, is likely to improve long-term outcomes
a lower dose and weekly increases are recommended. for patients.
Although less well studied, gabapentin may be a cost-
effective alternative with a similar side-effect profile.17 References

Opioids 1. Arnold LM, Gebke KB, Choy EH. Fibromyalgia: Management strate-
Tramadol, a weak opioid with mild serotonin-noradrenalin gies for primary care providers. Int J Clin Pract. 2016;70(2):99-112.
re-uptake inhibitor activity, improved pain. Avoid stronger
opioids because of the lack of evidence supporting ef- 2. Vincent A, Benzo RP, Whipple MO, et al. Beyond pain in fibro-
ficacy and high risk of side effects and addiction. myalgia: Insights into the symptom of fatigue. Arthritis Res Ther.
2013;15(6):221.
Corticosteroids, NSAIDs, and tender point injections
There is no evidence for the efficacy of corticosteroids 3. Wolfe F, Smythe HA, Yunus MB, et al. The American College of
or nonsteroidal anti-inflammatory drugs in fibromyalgia Rheumatology 1990 Criteria for the Classification of Fibromyalgia.
syndrome, and these drugs should be avoided because Report of the Multicenter Criteria Committee. Arthritis Rheum.
of their significant side effects. Similarly, there is minimal 1990;33(2):160-72.
evidence of benefit for the injection of tender points
with local anaesthetic, corticosteroids or saline. 4. Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the
2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum.
Alternative therapies 2016;46(3):319-29.
Although the evidence from randomised control trials
is relatively weak, individual patients report a decrease 5. Choy E, Perrot S, Leon T, Kaplan J, et al. A patient survey of the im-
in pain and fatigue and/or improved sleep with regard pact of fibromyalgia and the journey to diagnosis. BMC Health Serv
to alternative treatments, including capsaicin gel, acu- Res. 2010;10:102.
puncture, hydrotherapy, meditation, yoga, qigong, tai
chi, and mindfulness training. A comprehensive review 6. Hauser W, Perrot S, Sommer C, et al. Diagnostic confounders of
of the evidence for these alternative therapies is offered widespread chronic pain: Not always fibromyalgia. Pain Rep.
in the EULAR revised recommendations.18 2017;2(3):e598.

Cannabinoids 7. Albrecht PJ, Rice FL. Fibromyalgia syndrome pathology and en-
Although a recent Cochrane review showed no con- vironmental influences on afflictions with medically unexplained
vincing evidence of improvement in fibromyalgia symp- symptoms. Rev Environ Health. 2016;31(2):281-94.
toms with nabilone (a synthetic cannabinoid), one study
showed benefit of cannabis with an increase in pain and 8. Karras S, Rapti E, Matsoukas S, Kotsa K. Vitamin D in fibromyalgia: A
stiffness, relaxation, lethargy, and mental health scores, causative or confounding biological interplay? Nutrients. 2016;8(6).
but with no significant changes in the Fibromyalgia Im-
pact Questionnaire.19,20 Many experts and patients con- 9. Okifuji A, Gao J, Bokat C, Hare BD. Management of fibromyalgia
sider cannabinoids to be a valid option, and, as with syndrome in 2016. Pain Manag. 2016;6(4):383-400.
other conditions, more clinical research is needed.
10. Hauser W, Perrot S, Clauw DJ, Fitzcharles MA. Unravelling fi-
When to refer bromyalgia-steps toward individualized management. J Pain.
2018;19(2):125-34.
Fibromyalgia can be confidently diagnosed and man-
aged by family physicians or primary healthcare pro- 11. Chen AT. The relationship between health management and infor-
fessionals. Referral to a rheumatologist or physician mation behaviour over time: A study of the illness journeys of peo-
is appropriate when there is a diagnostic difficulty – ple living with fibromyalgia. J Med Internet Res. 2016;18(10):e269.
particularly when an inflammatory joint disorder is sus-
pected. Patients with severe depression or anxiety will 12. Mengshoel AM, Vollestad NK, Forre O. Pain and fatigue induced by
benefit from referral to psychiatric services. Collabora- exercise in fibromyalgia patients and sedentary healthy subjects.
tion with other healthcare professionals, including physi- Clin Exp Rheumatol. 1995;13(4):477-82.
otherapists and psychologists, is recommended.
13. Bote ME, Garcia JJ, Hinchado MD, Ortega E. Fibromyalgia: Anti-
inflammatory and stress responses after acute moderate exercise.
PLoS One. 2013;8(9):e74524.

14. Hauser W, Klose P, Langhorst J, Moradi B, et al. Efficacy of different
types of aerobic exercise in fibromyalgia syndrome: A systematic
review and meta-analysis of randomised controlled trials. Arthritis
Res Ther. 2010;12(3):R79.

15. Welsch P, Uceyler N, Klose P, et al. Serotonin and noradrenaline
reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database
Syst Rev. 2018;2:CD010292.

16. Walitt B, Urrutia G, Nishishinya MB, et al. Selective serotonin reup-
take inhibitors for fibromyalgia syndrome. Cochrane Database Syst
Rev. 2015(6):CD011735.

17. Moore A, Wiffen P, Kalso E. Antiepileptic drugs for neuropathic pain
and fibromyalgia. JAMA. 2014;312(2):182-3.

18. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recom-
mendations for the management of fibromyalgia. Ann Rheum Dis.
2017;76(2):318-28.

19. Walitt B, Klose P, Fitzcharles MA, et al. Cannabinoids for fibromyal-
gia. Cochrane Database Syst Rev. 2016;7:CD011694.

20. Fiz J, Duran M, Capella D, et al. Cannabis use in patients with fi-
bromyalgia: effect on symptoms relief and health-related quality of
life. PLoS One. 2011;6(4):e18440.

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166 TREATMENT APPROACHES

Gout: diagnosis and management

ET Cornelissen tion (0.38 mmol/L) may result in the deposition of these
crystals in and around joints.1 Importantly, many people
MBChB (Stell), MMed (Int med Stell), FCP (SA)Cert Rheum (>90%) with hyperuricaemia do not form UA crystals or
develop gout. Factors controlling crystal formation are
Rheumatology Fellow, Division of Rheumatology, poorly understood, but genetic predisposition is likely
Tygerberg Academic Hospital, University of Stellenbosch, to play a role.2 Uric acid levels increase with age, and
Stellenbosch oestrogen is uricosuric; thus, gout is a disease of middle-
aged and older men and postmenopausal women.
B Hodkinson Hyperuricaemia and gout in premenopausal females
are most uncommon. Ninety percent of patients with
MBBCh, PhD, FCP (SA), Cert Rheum gout are renal under-excretors of UA, with only 10% of
cases due to increased production of UA (see Table 1).3
Professor and Head of Rheumatology Division,
Department of Medicine, University of Cape Town Decreased excretion of uric acid
and Groote Schuur Hospital, Cape Town
Genome-wide studies have identified polymorphisms
Gout is one of the most prevalent forms of inflamma- of genes encoding renal tubular urate transport genes,
tory arthritis. Effective and inexpensive therapy is widely such as uromodulin (URAT1: urate transporter 1) and glu-
available, yet gout is a major and increasing cause of cose transporter T9 (GLUT9: glucose transporter family
disability due to acute attacks, chronic destructive ar- member SLC2A9), as significant risk factors for gout.4
thropathy, tophi and renal disease.
Gout commonly occurs in the setting of metabolic
Epidemiology syndrome. Hypertension, obesity, dyslipidaemia, insulin
resistance and renal and cardiovascular disease are all
Gout affects more males than females and occurs world- associated with hyperuricaemia.
wide in 3-6% of men and 1-2% of women. The prevalence
of gout is increasing in both males and postmenopau- Medications causing an increase in URAT1 activity
sal females. Reasons for this growing global epidemic contribute to hyperuricaemia, including diuretics (both
include diet and lifestyle factors, particularly metabolic thiazide and loop diuretics), cyclosporine, and the anti-
syndrome and obesity, increased use of medications (es- tuberculosis drugs pyrazinamide and ethambutol. As-
pecially diuretics), and ageing of the population. pirin in low doses potentiates URAT1 activity, causing
hyperuricaemia, whereas high doses have a uricosuric
Pathogenesis effect by inhibiting URAT1.

Chronic elevation of serum uric acid (UA) above the sat-
uration point for monosodium urate (MSU) crystal forma-

Table 1. Causes of hyperuricaemia

Undersecretors (90%) Overproducers (10%)

Primary hyperuricaemia Idiopathic: disordered urate transport Rare X-linked genetic disorders:
HGPRT deficiency
PRPS overactivity

Secondary hyperuricaemia Metabolic causes: Diet rich in seafood, meat, alcohol
Hypertension High-fructose diet
Acidosis
Metabolic syndrome
Obesity

Renal causes: Lympho- or myeloproliferative diseases
Renal dysfunction (any cause)
Lead nephropathy
Polycystic kidney disease
Medullary cystic kidney
Familial juvenile hyperuricaemic
nephropathy

Drugs: Haemolysis
Alcohol Psoriasis
Diuretics Glycogen-storage diseases
Low-dose aspirin
Pyrazinamide, ethambutol
Levodopa-carbidopa
Beta-blockers
Cyclosporin

HGPRT – hypoxanthine-guanine phosphoribosyl transferase, PRPS – phosphoribosyl pyrophosphate synthetase

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TREATMENT APPROACHES 167

Overproduction of uric acid • Renal disease: urolithiasis (both uric acid and calcium Treatment approaches
stones), acute gouty nephropathy (usually in the set-
Enzyme deficiencies are rare, but can lead to early- ting of tumour lysis syndrome), and chronic uric acid
onset gout. Lesch-Nyhan syndrome is an X-linked reces- nephropathy.
sive deficiency of hypoxanthine-guanine phosphoribosyl
transferase (HGPRT), characterised by mental retardation Image published with the permission of the patient
with self-mutilation and early-onset gout with renal stones.
Another enzymatic abnormality that causes gout in the Figure 1a. Severe tophaceous gout involving the hands
young is phosphoribosyl pyrophosphate synthetase super-
activity, an X-linked dominant disorder with childhood or Diagnosis of gout
early adult-onset hearing loss, ataxia and gouty arthritis.
Demonstrating MSU in synovial fluid following joint aspi-
Secondary causes of hyperuricaemia include condi- ration or biopsy is the gold standard for diagnosis, and
tions linked to increased cell turnover, such as lympho- should be performed whenever possible. These nee-
or myeloproliferative disorders, tumour lysis syndrome dle-shaped crystals are negatively birefringent when
and inflammatory conditions, such as psoriasis and viewed with a polarising microscope. The ACR/EULAR
chronic haemolysis. 2015 classification criteria for gout allow the diagnosis
by weighting clinical, laboratory and radiographic fea-
A diet rich in purines, mainly from animal and seafood tures (see Table 3).7,8
origin, contributes to hyperuricaemia (see Table 2). Al-
cohol, particularly beer with its high purine load, is a big Serum uric acid, in conjunction with a clinical picture
risk for gout. Fructose increases uric acid, in addition to suggestive of gout, can be helpful in the diagnosis of
increasing obesity and insulin resistance. High-fructose gout, as most patients will have an elevated level at
corn syrup (HFCS), an artificial sweetener, is ubiquitous some stage. However, it is well known that the serum
in processed foods and soft drinks, and should be avoid- uric acid levels in patients with acute gout can be with-
ed. Interestingly, vegetable proteins (such as legumes), in normal limits. Also, hyperuricaemia does not confirm
are protective and should be encouraged in gout pa- the diagnosis of gout. It is therefore advised that serum
tients. Other foods to be encouraged are low-fat dairy uric acid levels be repeated a few weeks after initiating
products, coffee, plant oils – including olive and sun- treatment for acute gout, in patients fulfilling the criteria
flower oil, cherries, and vitamin C-rich foods.5 for the diagnosis of gout with normal uric acid levels.

Clinical patterns of hyperuricaemia Acute gouty arthritis and septic arthritis share clinical
and gout and laboratory features, and both tend to occur on
previously damaged joints. Any patient with an acute
Hyperuricaemia and gout have five clinical phases:6
• Asymptomatic hyperuricaemia: raised serum uric

acid levels without clinical symptoms.
• Acute arthritis: acute-onset, red, exquisitely painful

joint (usually affects lower limb joint initially – for ex-
ample, first metatarsophalangeal joint, knee or an-
kle) or bursitis.
• Intercortical gout: the asymptomatic period be-
tween acute gout episodes, but gout attacks be-
come more frequent and more severe over time.
• Chronic tophaceous gout: polyarticular form affect-
ing small and large joints with deformity and destruc-
tion (see Figure 1). Tophi may present on the hands,
feet, elbows, knees, ears (pinna), Achilles tendon –
and rarely have been described in atypical anatomi-
cal sites, e.g. spinal cord, heart valves.

Table 2. Diet and hyperuricaemia

Very high purine content High purine content Protective

Mussels Bacon Low-fat dairy (particularly yoghurt)

Clams Alcohol: beer >spirits >wine Vegetable purines, e.g. lentils

Lobster Liver, sweetbreads (pancreas) High doses of vitamin C

Anchovies High fructose-sweetened drinks, foods Cherry juice
containing HFCS

Herring Turkey Coffee

Sardines Veal

Salmon

HFCS: High-fructose corn syrup is found in condiments, e.g. tomato sauce, salad dressing, and steak sauce; cereal bars, energy and protein bars;
bread pastries; and breakfast cereals

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168 TREATMENT APPROACHES

ovitis, joint effusions and a “double contour” sign (uric
acid crystal deposition on hyaline cartilage) to support
the diagnosis of gout. Dual-energy computer tomog-
raphy (DECT) is a fairly new imaging modality used for
the diagnosis of gout and seems to have a high sensitiv-
ity and specificity, as quoted in some studies. It offers a
non-invasive method of detecting MSU crystals.11

Image published with the permission of the patient

Figure 1b. Large tophi involving the first metatar-
so­phalangeal joints of the feet

monoarthritis, where gout is suspected, should have Figure 2. Radiograph of feet – rat-bitten, large,
septic arthritis excluded, by aspirating joint fluid for mi- juxta-articular erosion with sclerotic base
croscopy, culture and sensitivity. and overhanging edge

Imaging modalities can assist with the diagnosis of
gout (see Figure 2).9,10 Joint radiographs may show evi-
dence of gout in the form of erosive disease (“rat-bitten
erosions”) and furthermore assist to differentiate gout
from other inflammatory arthritides, or reveal gout as a
concomitant diagnosis in patients with inflammatory ar-

thritides. Ultrasonography of joints can demonstrate syn-

Table 3. ACR EULAR Gout classification criteria7,8

Step 1: Entry criterion: The criteria below can only be used for patients presenting with at least one episode of swelling or tenderness
in a peripheral joint or bursa.
Step 2: The presence of monosodium urate crystals in a symptomatic joint or bursa (synovial fluid) or the presence of tophus: If this
clinical criterion is present, the classification of gout can be made without using Step 3.
Step 3: Weighted scoring of gout features: The diagnosis of gout is made if a total score of ≥8 is reached.

The pattern of joint/bursa involvement: Ankle or midfoot: Podagra:
score 1 score 2

Characteristics: One characteristic: Two characteristics: Three characteristics:
• Erythema overlying joint score 1 score 2 score 3
• Cannot bear to touch/pressure
• Difficulty walking/unable to use joint >0.6 mmol/L:
score 4
Time course of a typical episode: One typical episode: Recurrent typical
• Maximum pain within 24 hours score 1 episodes:
• Symptom resolution within 14 days score 2
• Complete resolution of symptoms between attacks

Clinical evidence of tophus: Present:
• Draining or chalk-like, subcutaneous nodule visible score 4

under the skin

Serum uric acid level: <0.24 mmol/L: 0.36- 0.48 mmol/L:
• Off treatment score -4 score 2
0.48-0.60 mmol/L:
score 3

Synovial fluid analysis: MSU negative: MSU-positive:
symptomatic joint/bursa aspirated score -2 sufficient criterion

Imaging: score 4
• Ultrasound detection: "double contour sign"
• Radiography of hands/feet: erosions, overhanging

edges, sclerotic margins
• DECT: MSU deposition

MSU – monosodium urate; DECT – dual energy computer tomography; mmol/L – millimoles per litre.

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TREATMENT APPROACHES 169

Management long the attack, traditional teaching has been to wait Treatment approaches
for two to four weeks after an attack has settled before
Once a confident diagnosis of gout has been made, starting ULT. Recent small studies, however, show that
the aim must be to manage the disease appropriately ULT can be started during an acute attack with no risk
and effectively. Lifestyle modification is vital, and the of aggravating the attack.15 The choice of therapies is a
following should be urgently addressed: xanthine oxidase inhibitor (XOI) or a uricosuric.
• Weight loss and regular exercise.
• Screen and address risk factors for comorbid meta- Xanthine oxidase inhibitors

bolic diseases: renal impairment, coronary artery dis- Allopurinol is the XOI of choice as first-line ULT for chronic
ease, heart failure, stroke, peripheral arterial disease, gout. Major adverse effects of allopurinol are the in-
obesity, hyperlipidaemia, hypertension, diabetes creased risk of gout flares, and a hypersensitivity rash,
and smoking. Gout is an independent risk factor for which includes Stevens-Johnson syndrome (SJS) and
all-cause mortality, and particularly the risk of cardio- toxic epidermal necrosis (TEN). Allopurinol should be ini-
vascular events beyond that which would be ex- tiated at 100 mg/day (50 mg/day in patients with chron-
pected from traditional comorbid cardiovascular risk ic kidney disease because of the risk of hypersensitivity
factors.12 Thus, hyperuricaemia is a red flag for cardio- rashes). Screening for HLA-B*5801 may be considered in
vascular disease, diabetes and kidney disease. patients of Asian descent to detect an increased risk of
• Dietary modifications (see Table 2). In general, pa- severe allopurinol hypersensitivity rash.
tients should be encouraged to increase their fluid in-
take to 2-3 litres per day, avoid all alcohol, eliminate Initiating ULT may precipitate an acute gout attack.
HFCS-containing, processed foods and exchange All patients should be educated on what to expect
animal-based proteins for plant-based proteins, such during the initiation phase of ULT to improve long-term
as legumes, nuts, tofu and low-fat dairy (1-2 servings compliance. Prophylactic therapy, in the form of colchi-
per day).5 cine (0.5-1 mg daily), should be prescribed for up to six
months, or until the uric acid level is below 0.4 mmol/L.
Acute gout attack Patients intolerant to colchicine can be offered low-
dose NSAIDs unless contra-indicated, to use should an
The aim of treatment is symptom relief – in other words, attack occur while initiating ULT.16
to reduce pain and swelling. Ice application is a benefi-
cial modality. Treatment depends on the renal and gas- Importantly, if an acute attack occurs, allopurinol
tro-intestinal status (particularly the presence of peptic should not be stopped, but rather continued alongside
ulcer disease) of the patient (see Figure 3). The choices the treatment for the acute attack. Patients and their
include: healthcare providers need to be educated about this
• Short-term (five days or until the attack has resolved), principle because otherwise a vicious cycle – acute at-
tack, initiation of ULT, a new attack, discontinuation of
high-dose, nonsteroidal anti-inflammatory agents ULT, recurrent attack – ensues, with little progress made
(NSAIDs) prescribed with a proton-pump inhibitor to prevent future attacks by lowering uric acid levels.
(PPI) as gastric protection.
• Colchicine 1  mg stat orally followed by 0.5  mg one The dose of allopurinol should be titrated upwards
hour later. Recently, research showed that the low- every two to five weeks. Recent data have shown that
er dose is as effective,13 with fewer gastro-intestinal allopurinol at a dose of ≤300  mg daily fails to achieve
side effects (particularly diarrhoea). Avoid colchicine an appropriate reduction in serum uric acid levels in
in severe renal dysfunction (GFR <30  ml/min) and approximately 30-50% of gout patients with normal re-
do not co-prescribe the drug with cyclosporine or nal function.14 A treat-to-target strategy is suggested
clarithromycin. where allopurinol is increased until a target serum uric
• In the case of contra-indications to colchicine or acid level of 0,36 mmol/L, or 0.30 in patients with tophi,
NSAIDs (e.g. renal impairment), prescribe intra-artic- is reached. Allopurinol can be prescribed in doses up to
ular corticosteroids or a short oral course (five days) 800 mg daily.
of a moderate dose (30-35 mg/day).
• Interleukin 1 inhibitors (anakinra, canakinumab) have Febuxostat is an alternative XOI with a much lower risk
been used successfully in acute gout flares where of hypersensitivity, but is expensive and not yet avail-
NSAIDs, colchicine and steroids are contra-indicated.14 able in SA.

Chronic tophaceous gout Uricosurics

Once an acute episode of gout has subsided, the deci- Probenecid can be used in the management of chron-
sion on chronic therapy needs to be addressed. Urate- ic gout, including combination therapy with XOI. It is
lowering therapy (ULT) is indicated in the following pa- contra-indicated in patients with a history of urolithiasis,
tients: patients who produce excess uric acid and who have
• Tophi (clinical or x-ray erosions) renal failure with an eGFR <50 ml/min.17,6 Pegloticase is a
• Recurrent gout episodes: ≥2 per annum [? Consid- pegylated uricase used for the management of severe
refractory gout and can be used in patients with renal
er earlier intervention in patients with comorbidities impairment. Its use is limited due to its cost.
and/or SUA level >8 mg/dL]14
• Urate nephropathy or nephrolithiasis Concomitant medication
Owing to fears that initiating ULT too soon may pro-
Where possible, drugs that cause hyperuricaemia should
be reviewed and discontinued. However, low-dose

HANDBOOK OF GENERAL MEDICINE VOL 1

170 TREATMENT APPROACHES

aspirin for cardio-protection should not be stopped; agement of asymptomatic hyperuricaemia. However,
diuretics may be difficult to withdraw in heart failure or there may be advantages in treating asymptomatic
renal insufficiency and should be prescribed continu- hyperuricaemia in patients with chronic kidney disease
ously at the lowest dose possible because intermittent and in the setting of post-acute myocardial infarction,
use of diuretics can precipitate gout flares. Drugs with and further studies are needed to inform future man-
mild uricosuric action include losartan (angiotensin re- agement guidelines.18,12
ceptor blocker), amlodipine (calcium-channel block-
er), statins and fenofibrates, and should be prescribed Goals of gout therapy
where possible.
Early aggressive treatment, lifestyle modification and
Asymptomatic hyperuricaemia comorbid disease-screening are key in the manage-
The management of asymptomatic hyperuricaemia is ment plan of gout. The goal for all patients with gout is
controversial. Currently, ULT is not advised for the man- to achieve a serum uric acid level of 0.36 mmol/L, with
a lower goal (0.30 mmol/L) for patients with severe/

Management of the acute attack:
AIM: rapid symptom control

NB: no change to ULT duiriing the acute attack

ICE, simple analgesics

No renal and GIT contra-indications

Renal dysfunction or high risk for PUD

NSAID x 5-7 days Colchicine 1 mg
stat po followed by
0.5 mg 1 hour later* Prednisone 30-35 mg Intra-ocular
daily for 5 days corticosteroids

Resolution of flare

Consider ULT initiation + flare
prophylaxis

*consider lower doses if diarrhoea
NSAID – nonsteroidal anti-inflammatory drug; PUD – peptic ulcer disease; GIT – gastro-
intestinal tract; ULT – urate-lowering therapy

Figure 3. Management of an acute gout attack
HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 171

tophaceous gout.14 Patients can be reassured that it is Treatment approaches
possible for attacks to stop and for tophi to resolve with
effective treatment.

When to refer

General practitioners and internal medicine specialists
often manage gout. Referral to a rheumatologist be-
comes necessary in the following situations:
• Failure to reach disease control with first-line therapy.
• Severe side effects on standard therapy.
• Severe tophaceous gout with the risk of functional

loss of joints, e.g. tendon rupture and loss of hand
function.

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spective – a review. J Adv Res. 2017;8(5):495-511.

2. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388 (10055):
2039-52.2.

3. Mandal AK, Mount DB. The molecular physiology of uric acid ho-
meostasis. Annu Rev Physiol. 2015;77:323-45.

4. So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;
120(6):1791-9.

5. Beyl RN Jr, Hughes L, Morgan S. Update on importance of diet in
gout. Am J Med. 2016;129(11):1153-8.

6. Klippel JH, et al. Primer on the rheumatic diseases. New York: Spring-
er-Verlag; 2008.

7. Neogi T, et al. 2015 Gout classification criteria: An American Col-
lege of Rheumatology/European League Against Rheumatism col-
laborative initiative. Ann Rheum Dis. 2015;74(10):1789-98.

8. Abrahams MN. Gout and hyperuricaemia. SAMJ. 2015;105(12).
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raphy in detecting gouty arthritis. The Egyptian Rheumatologist.
2013;35(2):71-5.
10. Nicolaou S, et al. Dual-energy CT: A promising new technique for
assessment of the musculoskeletal system. AJR Am J Roentgenol.
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11. Chou H, Chin TY, Peh WCG. Dual-energy CT in gout – a review of cur-
rent concepts and applications. J Med Radiat Sci. 2017;64(1):41-51.
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nostic markers among those with a recent acute myocardial infarc-
tion. Arthritis Res Ther. 2012;14(1)
13. Van Echteld I, et al. Colchicine for acute gout. Cochrane Data-
base Syst Rev. 2014;(8)
14. Richette P, et al. 2016 updated EULAR evidence-based recommenda-
tions for the management of gout. Ann Rheum Dis. 2017;76(1):29-42.
15. Hill EM, Sky K, Sit M, et al. Does starting allopurinol prolong acute
treated gout? A randomized clinical trial. J Clin Rheumatol. 2015;
21:120-5.
16. Nuki G, Doherty M, Richette P. Current management of gout: Prac-
tical messages from 2016 EULAR guidelines. Polish Arch Intern Med.
2017;127(4):267-77.
17. Khanna D, et al. 2012 American College of Rheumatology guide-
lines for management of gout. Part 1: Systematic nonpharmaco-
logic and pharmacologic therapeutic approaches to hyperurice-
mia. Arthritis Care Res. 2012;64(10):1431-46.
18. Jalal DI, et al. Uric acid as a target of therapy in CKD. Am J Kidney
Dis. 2013;61(1):134-46.

HANDBOOK OF GENERAL MEDICINE VOL 1

172 TREATMENT APPROACHES

Inflammatory arthritis: a practical approach
to the diagnosis and management

K Makan the challenges in diagnosing an inflammatory arthritis
when the symptoms are non-specific and inconclusive.
MBChB, FCP(SA), Cert Rheum(SA) This is significant, as there is a large and growing body
of evidence demonstrating the benefits of early treat-
Rheumatologist and Specialist Physician, ment of inflammatory arthritis; where early intervention
Division of Rheumatology, Department of Internal Medicine, can retard or even reverse the long-term course of the
Chris Hani Baragwanath Academic Hospital, disease.5-7
University of Witwatersrand, Johannesburg
This article discusses the importance of early recog-
Chronic inflammatory arthritis (IA) refers to a group of nition of inflammatory arthritis and provides a practical
diseases of auto-immune aetiology, characterised by approach to identifying and characterising inflamma-
inflammation of the joints, and often accompanied by tory joint disease, together with a simplified manage-
systemic manifestations. Rheumatoid arthritis (RA) ac- ment approach that can be applied to all forms of in-
counts for the vast majority of presentations, affecting flammatory arthritis.
approximately 0.5-1% of the population,1 with the spon-
dylo-arthropathies (ankylosing spondylitis [AS], psoriatic Early arthritis and the 'window
arthritis [PSA] and reactive arthritis [ReA]) and other sys- of opportunity'3,5-7
temic rheumatic diseases being far less common (see
Table 1). Early arthritis refers to an initial phase in disease presen-
tation, where the type of inflammatory arthritis cannot
Although clinical presentations may vary considera- readily be identified. This undifferentiated inflammatory
bly between the different types of inflammatory arthritis, arthritis may evolve into a specific rheumatic disease, or
they share a similar pathogenic process. Genetic fac- remit spontaneously.
tors (HLA-DRB1 in RA, HLA-B27 in AS) and environmental
triggers (cigarette-smoking in RA, infective agents - e.g. For the subgroup of inflammatory arthritis that is likely
Chlamydia trachomatis - in ReA) interact to incite an to evolve, this period, usually within the first three to six
auto-immune response, directing cytokine-mediated months of symptom onset, is considered a “therapeutic
inflammation to the joints, which if untreated, can lead window of opportunity”, where early aggressive man-
to significant joint damage and disability. agement can significantly improve the outcome of dis-
ease.
Despite significant advances in the treatment of in-
flammatory arthritis, the burden of the disease is on the Data from approximately 100 studies have shown that
rise, and according to the 2010 Global Burden of Dis- introduction of disease-modifying anti-rheumatic drugs
ease Survey, arthritis is the second leading cause of dis- (DMARDs), frequent follow-up and treatment adjust-
ability as measured by years lived with disability. This bur- ment during this period, result in improved function and
den is notably higher in developing nations, including quality of life, reduced disability and long-term joint
South Africa, where diagnoses are often delayed due damage. Studies in RA document the presence of ra-
to poverty, poor education, cultural beliefs and lack of diographic erosions in as many as 75% of patients within
access to healthcare.2 the first two years of symptom onset, implying damage
occurs early in the disease. Also, the demonstration
However, the problem of delayed diagnosis is not of comparative toxicity between nonsteroidal anti-in-
limited to the developing nations. Data from numer- flammatory drugs (NSAIDs) and DMARDs, suggests that
ous sites in Europe show delays of up to six months be- lengthy symptomatic treatment without specific man-
fore consultation with a rheumatologist.3,4 Clinicians, agement is not without its detrimental side effects.3
including experienced rheumatologists, will admit to

Table 1. Causes of inflammatory arthritis

Rheumatoid arthritis Systemic rheumatic illnesses
Crystal-induced arthritis (gout, CPPD)*: - Systemic lupus erythematosus
Inflammatory osteoarthritis - Systemic vasculitis
Post-infectious or reactive arthritis*: - Poly-/dermatomyositis
- Still’s disease
- Enteric infection - Behcèt's syndrome
- Urogenital infection - Relapsing polychondritis
- Rheumatic fever
- Post-streptococcal Other systemic illnesses
Other spondyloarthropathies - Sarcoidosis
- Ankylosing spondylitis - Malignancy
- Psoriatic - Palindromic rheumatism
- Enteropathic - Hypothyroidism

* – Usually acute. Can progress to chronic arthritis. CPPD – calcium pyrophosphate deposition

HANDBOOK OF GENERAL MEDICINE VOL 1

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information approved by SAHPRA, 29 July 2005. FMA478/05/2018.

174 TREATMENT APPROACHES

Clinical research has defined features that predict Day-to-day variation of joint signs, severe tenderness
progression to a more destructive form of arthritis. Fe- on attempted examination and non-arthritic swelling
male gender, high affected joint counts, hand involve- (e.g. ankle oedema) can confound assessment. Con-
ment, cigarette-smoking, a high acute-phase response, sequently, the metacarpophalangeal (MCP) “squeeze
positive serology and radiograph­ic erosions are predic- test” was devised as a screening test for inflammatory
tive of progression to RA. Recognising these features arthritis. Pressure applied across the metacarpal or met-
should prompt early intervention and rapid referral. Simi- atarsal heads will induce pain if the test is positive, and
larly, elements that suggest a milder, self-remitting form should arouse suspicion of an inflammatory arthritis (see
of arthritis must be recognised, to avoid overtreatment. Figure 2).3

Diagnostic approach to Figure 2. The metacarpophalangeal squeeze test: direct
inflammatory arthritis7-9 pressure applied with the thumb and index finger across
Clinical assessment 4 MCP joints

A thorough history and examination are integral to the Appreciating the value of this clinical test, Arthritis Re-
diagnosis of inflammatory joint conditions. An evalua- search UK developed the “S-factor tool” to assist non-
tion of the pattern of joint involvement may help define rheumatologists in recognising inflammatory arthritis
the underlying aetiology, but most importantly establish (see Table 3).1,10
if the arthritis is of an inflammatory nature. Numerous
features suggest joint inflammation, none more impor- Another 8-item questionnaire developed in Europe in-
tant than the detection of synovitis. Table 2 lists clinical corporates five clinical features to identify inflammation
clues to inflammatory arthritis. (see Table 4).11

Recognising synovitis (diffuse swelling and tenderness Pattern recognition is important in distinguishing vari-
over the joint signifying synovial membrane inflamma- ous forms of inflammatory arthritis. Consider:
tion) can be difficult for the untrained medical practi- • Onset and evolution of joint symptoms (acute or
tioner (see Figure 1).
chronic; additive, migratory or intermittent)
Figure 1. Knee synovitis • Number of joints involved (oligo-articular, two to four

joints or polyarticular, ≥5 joints)
• Type of joints involved (axial or peripheral/large or

small)
• Symmetry

Table 2. Clinical clues to suggest an inflammatory arthritis

History Younger age Examination
• Diffuse or multifocal symptoms • Fever
• Rest pain and nocturnal pain • Skin rashes, oral ulcers, alopecia
• Prolonged morning stiffness >1 hour • Conjunctivitis, uveitis, sinusitis
• Constitutional symptoms • Warm and swollen joints
• Recent infection or surgery • Overlying erythema
• No previous trauma • Small hand joint involvement
• Positive family history • Other organ involvement
•

Table 3. S-factors screening for early inflammatory arthritis1,10

Factor Sign, symptom

Stiffness Early morning stiffness lasting >30 minutes

Swelling Persistent swelling of one or more joint/s particularly hand joints

Metacarpophalangeal (MCP) squeeze test Tenderness on squeezing across all 4 MCP joints

Metatarsophalangeal (MTP) squeeze test Tenderness on squeezing across metatarsal heads

Referral to a rheumatologist is recommended if ≥1 factor is present

HANDBOOK OF GENERAL MEDICINE VOL 1

Trust the science behind the original etoricoxib…1,2
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fast and lasting2,3,a
pain relief

Excellence in Efficacy1,2,4-11

a in acute pain

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IN PATIENTS ≥ 16 YEARS OF AGE 2

ACUTE CHRONIC

For the short-term treatment of: 2 For the symptomatic relief of: 2
Moderate to Severe Acute Osteoarthritis
30 or 60 mg once daily
Post-operative Dental Surgery Pain Rheumatoid Arthritis
90 mg once daily 90 mg once daily
Acute Pain
For the treatment of: 2
90 or 120 mg once dailyb Ankylosing Spondylitis
Acute Gouty Arthritis 90 mg once daily
120 mg once dailyb
bLimited to a maximum of 8 days treatment.
Primary Dysmenorrhoea
120 mg once dailyb

Doses shown are the maximum recommended daily dose. Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been
studied. As the cardiovascular risks of EXINEF may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.

REFERENCES: 1. Approved ARCOXIA package insert, October 2013. 2. Approved EXINEF package insert, November 2014. 3. Malmstrom K, Sapre A, Coughlin H, et al. Etoricoxib in acute pain associated with dental surgery: a randomized, double-blind, placebo- and active comparator-controlled dose-ranging study. Clin Ther. 2004;26(5):667–679. 4. Lin H-Y, Cheng
T-T, Wang J-H, et al. Etoricoxib improves pain, function and quality of life: results of a real-world effectiveness trial. Int J Rheum Dis. 2010;13(2):144-150. 5. Moore RA, Moore OA, Derry S, et al. Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice.
Ann Rheum Dis. 2010;69:374-379. 6. Nor Azlin MI, Maryasalwati I, Norzilawati MN, et al. The efficacy of etoricoxib vs mefenamic acid in the treatment of primary dysmenorrhoea: A randomised comparative trial. Journal of Obstetrics and Gynaecology. 2008;28(4):424-426. 7. Viscusi ER, Frenkl TL, Hartrick CT, et al. Perioperative use of etoricoxib reduces pain
and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study. Curr Med Res Opin. 2012;28(8):1323-1335. 8. Bingham CO, Sebba AI, Rubin BR, et al. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled,
non-inferiority studies. Rheumatology. 2007;46:496–507. 9. Van der Heijde D, Baraf HSB, Ramos-Remus C, et al. Evaluation of the Efficacy of Etoricoxib in Ankylosing Spondylitis. Arthritis & Rheumatism. 2005;52(4):1205-1215. 10. Daniels SE, Bandy DP, Christensen SE, et al. Evaluation of the Dose Range of Etoricoxib in an Acute Pain Setting Using the Postoperative
Dental Pain Model. Clin J Pain. 2011;27(1):1–8. 11. Matsumoto AK, Melian A, Mandel DR, et al. for Etoricoxib Rheumatoid Arthritis Study Group. A randomised, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol. 2002;29(8):1623–1630.

SELECTED SAFETY INFORMATION: CONTRAINDICATIONS: EXINEF is contraindicated in: patients with known hypersensitivity to any of the excipients of EXINEF; patients with active peptic ulceration or gastrointestinal (GI) bleeding; patients with severe hepatic dysfunction (Child-Pugh score > 9 or serum albumin < 25 g/l); patients with estimated creatinine clearance

< 30 ml/min; patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioedema or urticaria following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) including EXINEF; hypertension which has not been adequately controlled; pregnancy and lactation; children and adolescents under 16 years of age; patients with

inflammatory bowel disease; patients with congestive heart failure (NYHA II - IV); established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease; perioperative analgesia in the setting of coronary artery bypass surgery (CABG). WARNINGS AND SPECIAL PRECAUTIONS: EXINEF may predispose to cardiovascular events, gastrointestinal

events or cutaneous reactions which may be fatal. Long-term administration of NSAIDs such as EXINEF has resulted in renal papillary necrosis and other renal injury. Under conditions of compromised renal perfusion, administration of EXINEF may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow and thereby impair renal function. Caution

should be used when initiating treatment with EXINEF in patients with dehydration. Fluid retention, oedema and hypertension have been observed in patients taking EXINEF. All NSAIDs, including EXINEF, can be associated with new onset or recurrent congestive cardiac failure. Special attention should be paid to blood pressure monitoring during treatment with EXINEF.

Clinical trials suggest that the selective COX-2 inhibitor class of medicines such as EXINEF are associated with an increased risk of thrombotic events (especially myocardial infarction (MI) and stroke). As the cardiovascular risks of selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily

dose should be used. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with EXINEF after careful consideration. EXINEF is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. When using EXINEF in the elderly and in

patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be intensified. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of EXINEF. Upper GI complications, some of them resulting in fatal outcome, have occurred in patients treated with EXINEF. There is an increase in the

risk of gastrointestinal adverse effects when EXINEF is taken concomitantly with aspirin (even at low doses). Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 or more times the upper limit of normal) have been reported in approximately 1 % of patients in clinical trials treated for up to one year with EXINEF 60 and

90 mg daily. EXINEF may mask fever and other signs of inflammation or infection. EXINEF Tablets contain lactose. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take EXINEF. The use of EXINEF is not recommended in fertile women attempting to conceive. SIDE EFFECTS: In

clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with EXINEF for one year or longer. Very common (≥ 1/10) and Common (≥ 1/100, < 1/10) reported effects: alveolar osteitis, oedema/fluid retention, dizziness, headache, palpitations, hypertension, gastrointestinal disorders (e.g. abdominal pain, flatulence, heartburn), diarrhoea,

dyspepsia, epigastric discomfort, nausea, ecchymosis, asthenia/fatigue, flu-like disease, increased ALT, AST. EXINEF® 30 Tablet is not marketed.

MSD (Pty) Ltd (Reg. No. 1996/003791/07), For full prescribing information refer to the package insert

Private Bag 3, Halfway House, 1685. Tel: 011 655 3000. www.msd.co.za approved by the Medicines Regulatory Authority.

S3 EXINEF – Reg. No’s: 30 mg – 44/3.1/0898, 60 mg – 44/3.1/0899, 90 mg – 44/3.1/0900, 120 mg – 44/3.1/0901. Each EXINEF tablet contains 30 mg, 60 mg, 90 mg or 120 mg of etoricoxib. S3 ARCOXIA – Reg. No’s: 30 mg – 44/3.1/0063,
60 mg – 37/3.1/0399, 90 mg – 37/3.1/0400, 120 mg – 37/3.1/0401. Each ARCOXIA tablet contains 30 mg, 60 mg, 90 mg or 120 mg of etoricoxib. Copyright © 2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ,
USA. All rights reserved. ZA-CXB-00008 04/21

Betamethasone 3 mg/ml as Betamethasone Sodium MUSCULOSKELETAL
Phosphate and Betamethasone Acetate 3 mg/ml DERMATOLOGICAL
RESPIRATORY

1 ml Celestone® Soluspan® delivers
approximately 6 mg Betamethasone

NAPPI CODES

1 ml 712785001
2 ml 713171006
5 ml 711231002

and 1

INDICATIONS: CELESTONE® SOLUSPAN® is indicated in the treatment of severe or acute rheumatic, dermatologic and allergic conditions. CONTRAINDICATIONS: CELESTONE® SOLUSPAN® Injection is contraindicated in patients with systemic fungal infections, in patients hypersensitive to betamethasone
sodium phosphate, betamethasone acetate, other corticosteroids, or to any component of this product. Not for use in conditions ordinarily considered contraindicated to corticosteroid therapy. The anticipated clinical improvement must be weighed against the possibility of undesirable corticosteroid effects.
The safety in pregnancy and lactation has not been established. WARNINGS AND SPECIAL PRECAUTIONS: CELESTONE® SOLUSPAN® Injection is not for intravenous or subcutaneous use. Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids.
Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness and stroke. Rare instances of anaphylactoid/anaphylactic reactions with a possibility of shock have occurred in patients receiving parenteral corticosteroid therapy. Strict aseptic technique
is mandatory in the use of CELESTONE® SOLUSPAN® Injection. Dosage adjustments may be required with remission or exacerbation of the disease process, the patient’s individual response to therapy and exposure of the patient to emotional or physical stress such as serious infection, surgery or injury.
Corticosteroids may mask some signs of infection, and new infections may appear during use. When corticosteroids are used, decreased resistance and inability to localise infection may occur. Prolonged corticosteroid use may produce posterior subcapsular cataracts (especially in children), glaucoma with

possible damage to the optic nerves, and may enhance secondary ocular infections due to fungi or viruses. Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention and increased excretion of potassium. All corticosteroids increase calcium excretion. While on

corticosteroid therapy patients should not be vaccinated against smallpox. Other immunisation procedures should not be undertaken in patients receiving corticosteroids, especially high doses. However, immunisation procedures may be undertaken in patients who are receiving corticosteroids as replacement

therapy e.g. for Addison’s disease. Exposure to chickenpox and measles should be avoided in patients especially children, on immunosuppressant doses of corticosteroids. Use in active tuberculosis is restricted to fulminating or disseminated TB in conjunction with an appropriate anti-TB regimen. Reactivation
of disease may occur in patients with latent tuberculosis or tuberculin reactivity. The lowest possible dose of corticosteroid should be used to control the condition under treatment; when dosage reduction is possible, it should be gradual. The effects of CELESTONE® SOLUSPAN® are enhanced in patients with
hypothyroidism or in those with cirrhosis. Psychic derangements may appear with corticosteroid therapy. CELESTONE® SOLUSPAN® should be used with caution in ocular herpes simplex, non-specific ulcerative colitis, abscess or other pyogenic infection, diverticulitis, fresh intestinal anastomoses, active or
latent peptic ulcer, renal insufficiency, hypertension, osteoporosis and myasthenia gravis. SIDE EFFECTS: Fluid and electrolyte disturbances: Sodium retention, potassium loss, hypokalaemic alkalosis, fluid retention, congestive heart failure in susceptible patients, hypertension. Musculoskeletal: Muscle
weakness, corticosteroid myopathy, loss of muscle mass, aggravation of myasthenic symptoms in myasthenia gravis, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathologic fracture of long bones, tendon rupture, joint instability (from repeated intra-articular
injections). Gastrointestinal: Hiccups, peptic ulcer with possible subsequent perforation and haemorrhage, pancreatitis, abdominal distention, ulcerative oesophagitis. Dermatologic: Impaired wound healing, skin atrophy, thin fragile skin, petechiae and ecchymoses, facial erythema, increased sweating,
suppressed reactions to skin tests, reactions such as allergic dermatitis, urticaria, angioneurotic oedema. Neurologic: Convulsions, increased intracranial pressure with papilloedema (pseudotumor cerebri) usually after treatment, vertigo, headache. Endocrine: Menstrual irregularities, development of
Cushingoid state, suppression of foetal intrauterine or childhood growth, secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements of insulin
or oral hypoglycaemic agents in diabetes. Ophthalmic: Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos, vision blurred. Metabolic: Negative nitrogen balance due to protein catabolism. Psychiatric: Euphoria, mood swings, severe depression to frank psychotic
manifestations, personality changes, insomnia. Other: Anaphylactoid or hypersensitivity and hypotensive or shock-like reactions.

REFERENCES: 1. Approved CELESTONE® SOLUSPAN® Injection package insert. For full prescribing information refer to the package insert
approved by the Medicines Regulatory Authority

MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, Halfway House, 1685 I Tel: 011 655 3000 I www.msd.co.za

Celestone® Soluspan® Injection S4 Each ml contains 3 mg betamethasone as betamethasone sodium phosphate (in solution) and 3 mg betamethasone acetate (in suspension). Ref. No. G2963 (Act 101/1965).

Copyright © 2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All rights reserved. ZA-XTE-00002 05/21

TREATMENT APPROACHES 177

Table 4. Screening tool for inflammatory arthritis11 Treatment approaches

The presence or absence of the following items:
• Early morning stiffness >1 hour
• Characteristic distribution for inflammatory joint disease
• First-degree relative with inflammatory joint disease
• Clinical evidence of synovitis
• ESR ≥20 mm/1st h (men), ≥30 mm/1st h (women)
• Positive rheumatoid factor (≥80)
• Erosions on hands or feet x-ray
• Benefit from NSAIDs or steroids

* The presence of three or more items points to a diagnosis of inflammatory arthritis with a sensitivity of 97%, a specificity of 55%, a positive predictive
value of 49% and a negative predictive value of 97%.

• Presence of inflammatory back pain (IBP) - onset in early (<2 years of symptoms) RA, while in established
younger than 40 years, insidious onset, associated RA the majority of patients are RF-positive. ACPA has a
stiffness, improvement with exercise and NSAIDs, no much better specificity. Both tests are valuable in early
improvement with rest and pain at night arthritis as predictors of progression to RA and prognos-
ticating disease severity. However, it should be kept in
• Peri-articular involvement (tendons, ligaments, mus- mind that the diagnosis of RA can be made without
cles, bones) positive serology (seronegative RA). A positive HLA B27
can support a SPA diagnosis, but is not diagnostic and
• Extra-articular involvement (particularly skin and eye) has no role in routine screening of patients.
Table 5 summarises the typical patterns of involve-
X-rays are often performed in the initial work-up; how-
ment in inflammatory arthritis. Rheumatoid arthritis ever, early on they can be normal or show equivocal
typically presents as a chronic (≥6 weeks), symmetrical changes, such as peri-articular osteopaenia. Musculo-
polyarthritis involving the small hand joints in an addi- skeletal ultrasound and MRI are useful in detecting early
tive fashion. PSA might present similarly, although distal arthritis. Ultrasound is preferred for its lower cost, acces-
interphalangeal joint involvement and the presence of sibility and lack of radiation and can detect erosions
psoriasis is distinctive of PSA. Oligo-arthritis, particularly with a 96% accuracy. However, MRI is the modality of
involving the large lower limb joints asymmetrically, is choice when assessing for sacroiliac joint or early spinal
suggestive of a spondyloarthropathy (SPA) or gouty ar- involvement (spondylitis) in SPA. This subgroup of non-
thritis. If accompanied by IBP, enthesitis (inflammation of radiographic axial SPA, where changes are visible on
sites where tendons or ligaments attach to bone), con- MRI but not plain x-rays, is currently being investigated
junctivitis or uveitis, a SPA should be considered. History as a potential therapeutic period where the trajectory
of a recent gastro-intestinal or genito-urinary tract infec- of the disease can be altered.
tion can occur with ReA. Importantly, non-inflammatory
arthritis like osteoarthritis (OA) will not demonstrate syno- Synovial fluid analysis for crystals can diagnose gouty
vitis and is characterised by joint-line tenderness, crepi- arthritis. However, synovial biopsy is rarely indicated.
tus and bony overgrowth.
The role of classification criteria1,7,10,12
Finally, certain presentations can mimic inflammatory
arthritis and misdirect the examiner. Be aware of neu- Classification criteria have been designed for many of
rological disease, generalised pain syndromes such as the inflammatory arthritis types, primarily as a tool to
fibromyalgia, hypothyroidism and psychogenic causes. identify relatively homogenous cohorts for clinical re-
search. Nevertheless, they have found their way into
The role of special investigations clinical practice, assisting practitioners in the diagnosis
No single test that can definitively diagnose an inflam- of inflammatory arthritis.
matory arthritis is available. Investigations can, however,
lend support to a clinically suspected arthritis and help Newly developed classification criteria for RA and SPAs
differentiate between the various types of inflammatory focus on early disease identification, acknowledging the
arthritis. importance of early recognition and intervention. The in-
creased sensitivity of these criteria has come at the cost
A full blood count demonstrating an anaemia of a of reduced specificity, resulting in occasional over-diag-
chronic disorder or reactive thrombocytosis, elevated nosis and unnecessary referrals. These criteria are easily
acute-phase reactants – such as erythrocyte sedimen- accessible online; however, practitioners should be care-
tation rate and C-reactive protein – are non-specific ful not to rely entirely on criteria to make a diagnosis.
but useful markers of inflammation.
Management of inflammatory
Serological tests, such as rheumatoid factor (RF), an- arthritis1,7,8,10,12
tinuclear antibodies (ANA) and antibodies to citrulli-
nated peptide (ACPA or ACCP), should be used where Principles of management
clinically indicated. None of these tests is 100% sensitive The benefits of early aggressive treatment are undisputed;
or specific, and should not be the sole basis of diag- however, the converse is also true. Overtreatment with
nosis. RF can be elevated in numerous other inflamma-
tory and chronic infective conditions, in smokers and HANDBOOK OF GENERAL MEDICINE VOL 1
any person over 60 years. Also, RF is frequently negative

178 TREATMENT APPROACHES

Table 5. Classic presentations of the common inflammatory arthritides9

Disease Clinical features Investigations X-ray changes

Rheumatoid • Especially in perimenopausal • Anaemia, • Soft-tissue swelling
arthritis • Juxta-articular osteopaenia
females and male smokers thrombocytosis • Uniform joint-space narrowing
• Marginal erosions
• Early morning stiffness • Elevated CRP/ESR

• Symmetrical polyarthritis • RF-positive (80%)

• MCPJ, PIPJ, wrists, elbows,

shoulders, knees, ankles and MTPJ

• Swan-neck and boutonniere

finger deformities in established

disease

• Subcutaneous nodules

Ankylosing • Young males <40 years • Anaemia • Squaring of the vertebrae and loss
spondylitis • Inflammatory back pain
• Elevated CRP/ESR of lumbar lordosis
and stiffness, with reduced
spinal mobility later in disease may be present • Vertical and bilateral
(“question mark” posture)
• Peripheral arthritis usually • HLA B27-positive (90%) syndesmophytes
asymmetric, large lower limb
and oligo-articular • Fusion of the anterior longitudinal
• Enthesitis or plantar fasciitis
prominent ligament
• Dactylitis, conjunctivitis and
uveitis may be present • “Bamboo spine” in established
• Good response to NSAIDs
disease

• Sacroiliitis usually bilateral

and symmetrical

• Enthesopathy “whiskering”

Reactive arthritis • Young males • Anaemia, • Usually asymmetric involvement

• Preceding GI or genito-urinary thrombocytosis • Soft-tissue swelling

tract infection • Elevated CRP/ESR • Bony proliferation

• Peripheral arthritis predominates – • HLA B27-positive (50%) • Sacroiliitis often asymmetric

usually asymmetrical, oligo- • Enthesopathy

articular lower limb arthritis. May

be polyarticular and involve small

hand joints.

• Dactylitis, conjunctivitis, urethritis,

uveitis and “keratoderma

blenorrhagicum”

• Enthesitis

• Good response to NSAIDs

Psoriatic arthritis • Peak onset: 4-5th decade • Anaemia • Soft-tissue swelling
• Both sexes
• Early morning stiffness • Elevated ESR/CRP • Periosteal reaction
• Asymmetric oligo/polyarthritis
• DIPJ, PIPJ, wrists, knees, IPJ • RF and ANA-negative • Dactylitis
• Dactylitis
• Nail- pitting/ridging • HLA B27-positive (50%) • Marginal erosions
• Psoriasis plaques
• Uveitis and enthesitis • Exuberant peri-articular new bone

formation

• “Pencil-in-cup” deformity

• Arthritis mutilans

• Asymmetric sacroiliitis

• Spine – “jug-handle”

syndesmophytes

Gouty arthritis • Postpuberty males, • Elevated WCC, ESR/ • Asymmetric soft-tissue swelling

postmenopausal females CRP (during an acute • “Punched out” peri-articular

• Risk factors: obesity, attack) erosions

hypertension, beer, diuretics • Elevated serum urate

• 1st MTPJ, DIPJ, PIPJ, wrists, knees, • Urate crystals in

ankles, midfoot synovial fluid/tophi

• Tophi

SLE arthritis • Peak onset: 3-5th decade • Anaemia; low WCC/ • Soft-tissue swelling
• Female preponderance
• Early morning stiffness lymphopaenia • Joint-space narrowing
• Symmetrical polyarthritis
• PIPJ, MCPJ, wrists, elbows, • Elevated ESR/CRP • No erosions

shoulders, knees, ankles and • ANA-positive (97%)
MTPJ
• Correctable hand deformities
• Malar/discoid rash

DIPJ – distal interphalangeal joint; PIPJ – proximal interphalangeal joint; IPJ – interphalangeal joint; MCPJ – metacarpophalangeal joint;
MTPJ – metatarsophalangeal joint; WCC – white cell count; ESR – erythrocyte sedimentation rate; CRP – C-reactive protein; RF – rheumatoid factor;
ANA – antinuclear antibody; SLE – systemic lupus erythematosus

HANDBOOK OF GENERAL MEDICINE VOL 1

IMPROVE mgaFeriknrseettrib5c,r6atonded
CLINICAL
OUTCOMES,
DELAY DISEASE
PROGRESSION1

• Part of the guideline-recommended first treatment
strategy for active RA2

• As effective as MTX and equally well-tolerated3,4

• Effective alone and in combination with other DMARDs2

• Convenient once-daily dosing5

RHEUMALEF
Leflunomide

GET A GRIP ON
RHEUMATOID ARTHRITIS

RA – rheumatoid arthritis, MTX – methotrexate, DMARD – disease-modifying antirheumatic drug
References:
1. Osiri M, Shea B, Welch V, et al. Leflunomide for the treatment of rheumatoid arthritis (Review). Cochrane Database of Systematic Reviews 2002;3:CD002047.
2. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960-977.
3. Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology 2005;44:280-286.
4. Alfaro-Lara R, Espinosa-Ortega HF, Arce-Salinas CA. On behalf of the PRECIS study group. Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis.

Reumatol Clin 2017. http://dx.doi.org/10.1016/j.reuma.2017.07.020
5. Rheumalef Tablets approved package insert. 2015.
6. Reference on request.
S4 Rheumalef 10 Tablets. Each film-coated tablet contains leflunomide 10 mg. Reg. No. 45/3.1/0404.
S4 Rheumalef 20 Tablets. Each film-coated tablet contains leflunomide 20 mg. Reg. No. 45/3.1/0405.
For full prescribing information refer to the package insert approved by the medicines regulatory authority. 201807021087077.
Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Tel. +27 11 635 0000. www.adcock.com.

180 TREATMENT APPROACHES

potentially toxic drugs, in particular corticosteroids, should Glucocorticoids
be avoided where the diagnosis is unclear. Fortunately,
patients with ill-defined rheumatic symptoms seldom pro- Low-dose oral prednisone (≤7.5 mg/day) is appropriate
gress to develop serious complications or disability.13 in early arthritis to potentiate the effect of DMARDs, or
in established RA as “bridging therapy” upon initiation
The overarching principle in inflammatory arthritis of DMARDs. There is no role for glucocorticoids (GCs)
management is goal-directed therapy. This is well estab- as monotherapy for the treatment of RA, and doses
lished in RA where the “treat to target” strategy is widely >10 mg/day should never be used to control early ar-
accepted. Evidence suggests that obtaining tight con- ticular disease or flares. Intramuscular glucocorticoids
trol of disease, with a pre-defined goal of remission or (80-120 mg Depo-Medrol) may be used as an alterna-
low disease activity to drive disease-management de- tive to oral prednisone. Intra-articular steroids are useful
cisions, allows for better control of disease than routine to control joint flares. Glucocoticoids, in moderate to
clinic care. Disease activity is assessed by joint counts, high doses, are frequently used to control extra-articular
inflammatory markers and questionnaires to assess manifestations of the disease. There is no role for ster-
functional status. This intensive control strategy results in oids in AS or PSA, and their withdrawal can potentially
lower disease activity, better physical function and less induce a flare in psoriasis.12
structural damage, particularly when commenced ear-
ly. This strategy is increasingly being explored with other Conventional synthetic DMARDs
studies on inflammatory arthritis.
Disease-modifying anti-rheumatic drugs (DMARDs) are
A practical approach to the management of inflam- agents that can reduce or prevent joint damage and
matory arthritis is summarised below: preserve joint function. Conventional synthetic DMARDs
are listed below and summarised in Table 6.
Initial treatment should control pain and inflamma-
tion. Nonsteroidal anti-inflammatory drugs (NSAIDs), to- Methotrexate (MTX) is the drug of choice in RA due to
gether with simple analgesics such as paracetamol, are its excellent efficacy and safety profile. It is also widely
used first-line. used in PSA, despite a lack of evidence to support its
use. There is no role for MTX in other forms of SPA.
Introduce DMARDs early, ideally within six weeks of
symptom onset and by a rheumatologist or experi- Antimalarials (chloroquine or hydroxychloroquine) are
enced physician. frequently prescribed for lupus arthritis. In RA, they are
used as add-on therapy, when MTX alone is insufficient.
Initially, follow-up visits should be frequent (one- to There is no role for antimalarials in the treatment of SPAs.
three-monthly) to assess drug tolerability and safety, as
well as response to treatment. Doses can be escalated Sulphasalazine (SSZ) is effective as monotherapy in RA
and treatment added to achieve a target of low dis- when MTX is contra-indicated or as part of combination
ease activity. Once stable, four to six-monthly visits are DMARD therapy. It is also useful for treating peripheral
sufficient. joint involvement in SPAs.

Patient education, ideally by a rheumatology nurse, Leflunomide may be prescribed as monotherapy or
is paramount to ensure successful outcomes. Shared co-prescribed with MTX in the treatment of RA and PSA.
decision-making allows patients to participate in their
treatment, thus considering patient’s values and prefer- Biological DMARDs
ences over and above best scientific evidence.14
These are proteins directed against specific cytokines
Patients with inflammatory arthritis have an increased or their cell receptors. The most widely used biological
risk of cardiovascular morbidity. Uncontrolled severe DMARDs are those inhibiting tumour necrosis factor (or
joint inflammation, extra-articular disease, physical in- anti-TNF agents). In RA, these drugs show similar efficacy
activity and corticosteroid use contribute to the risk of to MTX, although the effects on radiographic progression
cardiovascular events. Controlling disease activity has appear to be higher and responses can be achieved
been shown to decrease cardiovascular risk, however more rapidly. Moreover, the combination of an anti-TNF
traditional risk factors, including smoking, hypertension, agent and MTX produces benefits greater than either
diabetes mellitus and dyslipidaemia, need to be man- alone. In SPA patients, where there is a lack of response
aged accordingly. to NSAIDs, anti-TNF therapy has been shown to improve
symptoms and retard radiographic progression.
Finally, management must involve a multidisciplinary
team which includes physiotherapy, occupational ther- A major side effect of anti-TNF therapy is an increased
apy, podiatry and psychology. susceptibility to infection, particularly tuberculosis (TB).
All patients should be screened for TB before initiating
Drug therapies in inflammatory arthritis treatment.

Nonsteroidal anti-inflammatory drugs Alternatives to the anti-TNF agents include agents
blocking cytokines IL1, IL6, IL17, IL12/23, co-stimulatory
In rheumatoid arthritis, NSAIDs should be used at the low- molecules, as well as anti-CD20, a B lymphocyte marker.
est effective dose and should be discontinued once
disease activity is controlled. Conversely, in SPA, NSAIDs Biological agents are considered if there is an inade-
are considered disease-modifying and should be used at quate response to conventional therapy. In SPA, this
maximal tolerable doses. Still, one must observe caution adjustment is made after three months, whereas in RA
when prescribing NSAIDs, particularly in the elderly and usually after six months. The choice of drug depends
patients with renal or cardiovascular disease. Use pro- on the safety profile and patient preference. If there is
ton pump inhibitors or COX-2 selective agents for gastric no response after six months, a switch to an alternative
protection. Worsening hypertension, renal injury and liver agent can be made.
dysfunction can complicate chronic NSAID use.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 181

Table 6. A summary of the synthetic DMARDs1,7 Treatment approaches

Drug Dose Indications Adverse effects Monitoring
Methotrexate (MTX) • Baseline FBC, urea and creatinine, LFT,
7.5-25 mg RA Common:
GI (mouth ulcers, mucositis, HIV, hepatitis-B and -C studies, chest
weekly orally or PSA nausea, vomiting) x-ray
Headaches • FBC, ALT, AST 1 month post drug
subcutaneous SLE Alopecia initiation, after that 3-6 monthly once
Marrow suppression stable dose/full liver-function tests
injection Hepatitis annually.
Rare: • Urea and creatinine 6-12 monthly.
Folic acid 5 mg Liver fibrosis • If ALT/AST elevated >3 x ULN, then
Pneumonitis stop drug; 2-3 x upper limit of normal,
weekly (not on Lung fibrosis reduce the dose.
Teratogenic • Recheck weekly and discontinue if
the same day as worsens or no improvement
Maculopathy • Annual eye check for maculopathy
MTX) GI (nausea, vomiting, • Caution in elderly and renal dysfunction
abdominal pain) • Safe in pregnancy
Antimalarials, 200 mg 3-5 times RA Headache, dizziness
e.g. chloroquine per week orally SLE Skin hyperpigmentation • FBC, ALT, AST 1 month post drug
Neuromyopathy initiation, after that 3-6 monthly once
Sulfasalazine 1-3 g per day RA ototoxicity stable dose/full liver function tests
orally PSA annually.
ReA GI (anorexia, nausea,
vomiting) • Discontinue if rash develops
Leflunomide 20 mg daily or RA Allergic skin rash • Safe in pregnancy
alternate daily SLE Marrow suppression
PSA Liver toxicity • Baseline FBC, urea and creatinine, LFT,
Decreased sperm count HIV, hepatitis-B and -C studies, chest
Pneumonitis x-ray and blood pressure

GI (nausea, vomiting) • FBC, ALT, AST 1 month post drug
Headache initiation, after that 3-6 monthly once
Hypertension stable dose/full liver function tests
Hepatitis annually.
Bone-marrow suppression
Alopecia • Blood pressure at each visit
Rashes • If ALT/AST elevated >3x ULN, then stop
Teratogenic
(Pregnancy should be drug; 2-3x upper limit of normal, reduce
delayed for at least one the dose.
year post discontinuation, • Recheck weekly and discontinue if
alternatively worsens or no improvement
cholestyramine washout.)

When to refer? References

Ideally, a rheumatologist should see all patients with a 1. Hodkinson B, van Duuren E, Pettipher C, Kalla AA. South African
suspected chronic inflammatory arthritis. Many large recommendations for the management of rheumatoid arthri-
rheumatology centres offer rapid-access clinics, where tis: An algorithm for the standard of care in 2013. S Afr Med J.
suspected arthritis can be screened to confirm or ex- 2013;103(8):576-585.
clude significant inflammatory arthritis.3
2. Mody GM. Rheumatology in Africa – challenges and opportunities.
The absence of abnormal investigations should not Arthritis Research & Therapy. 2017;19:49.
deter rheumatology referral, nor should a lengthy work-
up delay referral if enough concern exists. 3. Raza K, Filer A. Delays in assessment of patients with rheumatoid
arthritis: Variations across Europe. Ann Rheum Dis. 2011;70:1822-5.
Conclusion
4. Villeneuve E, Nam JL, Bell MJ, et al. A systematic literature review of
Early identification and treatment of inflammatory ar- strategies promoting early referral and reducing delays in the diag-
thritis can significantly improve outcomes, with drug- nosis and management of inflammatory arthritis. Ann Rheum Dis.
free remission being the ultimate goal. A comprehen- 2013;72:13-22.
sive history and examination, supported by available
screening tools and investigations, can fast-track diag- 5. Van Nies JA, Tsonaka R, Gaujoux-Viala C, et al. Evaluating relation-
nosis and permit the earlier introduction of effective ships between symptom duration and persistence of rheumatoid ar-
therapies. thritis: Does a window of opportunity exist? Results on the Leiden Early
Arthritis Clinic and ESPOIR cohorts. Ann Rheum Dis. 2015;74:806-12.

6. Emery P, Breedveld FC, Dougados M, et al. Early referral recommen-
dation for newly diagnosed rheumatoid arthritis: Evidence based
development of a clinical guide. Ann Rheum Dis. 2002;61:290-297.

7. Ajeganova S, Catrina AI, Huizinga TW. Early arthritis: Diagnosis and
management. In: Bijlsma JWJ, Hachulla E, & European League
Against Rheumatism. EULAR Textbook on Rheumatic Diseases. 2nd
edition. London: BMJ; 2015.

HANDBOOK OF GENERAL MEDICINE VOL 1

182 TREATMENT APPROACHES

8. Ledingham J, Snowden N, Id Z. Diagnosis and early management
of inflammatory arthritis. Practice BMJ. 2017;358:j3248 doi: 10.1136/
bmj.j3248.

9. Tikly M. A diagnostic approach to the common arthritic conditions.
SA Fam Pract. 2009;Vol 51 No 3.

10. Bester FCJ, Bosch FJ, Janse van Rensburg BJ. The specialist physi-
cian’s approach to rheumatoid arthritis in South Africa. Korean J
Intern Med. 2016;31:219-236.

11. Barbour JA, Binding J, Bridges M, et al. Evaluation of a screening
tool for inflammatory joint disease. Annals of the Rheumatic Diseas-
es. 2003;62:187-188.

12. Pisetsky DS, Ward MM. Advances in the treatment of inflammatory
arthritis. Best Pract Res Clin Rheumatol. 2012; 26(2): 251-261.

13. Mosca M, Tani C, Bombardieri S. Defining undifferentiated connec-
tive tissue diseases: A challenge for rheumatologists. Lupus. 2008,
17(4):278-280.

14. Zangi HA, Ndosi M, Adams J, et al. EULAR recommendations for pa-
tient education for people with inflammatory arthritis. Ann Rheum
Dis. 2015;74:954-962.

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 183

Lower backache: pathologies, diagnosis Treatment approaches
and treatment

AJ Vlok Fracture

MBChB; MMed(Neurosurgery) Stell; FC(Neurosurgery) Signs and symptoms pointed to both acute fractures
where violent trauma existed or insufficiency fractures
Associate Professor, Division of Neurosurgery, in osteopenic or osteoporotic patients. Severe pain with
University of Stellenbosch, Stellenbosch an immediate onset after minor injury should be investi-
gated.
GJ Vlok The red flags were:
• major or significant trauma
MBChB; MMed (Orth) Stell; FC (Orth) • use of steroids or immunosuppressors
• age over 70
Emeritus Professor, Division of Orthopaedic Surgery,
University of Stellenbosch, Stellenbosch Infection

Lower backache is one of the most common complaints The red flags were:
managed by general practitioners today. In 2015, ac- • fever
tivity-limiting backache had a reported prevalence of • use of corticosteroid or immunosuppressant therapy
7.3%, affecting an estimated 540 million people glob- • intravenous drug abuse
ally at any one time.1 It is now the commonest cause of • night pain
disability in the world. Middle- and lower-income coun-
tries are specifically affected where health systems are Cauda equina syndrome
burdened by infectious diseases, overpopulation and
limited resources.2 This diagnosis is supported by a thorough neurological
examination, which includes a rectal examination. The
The good news: In a meta-analysis including 11 166 following red flags cannot be ignored:
patients, near-resolution of pain was seen in most pa- • saddle anaesthesia (perineal numbness)
tients at six weeks when treated conservatively.3 How- • (sudden onset of) bladder dysfunction
ever, some pain was still reported by two-thirds of re-
spondents at three months. Unrelated to a specific cause

The bad news: A recurrence can be expected in 33% The red flags were:
of patients within one year of an episode.4 This is influ- • neurological fallout
enced by social, psychological and behavioural factors • pain under the age of 20
and seldom by an organic cause.5 The management of • spinal deformity
these co-factors does not entail quick-fixes and requires • backache not responding to conservative care
patience and co-operation from both the practitioner
and patient. Out of all episodes of backache, 85-90% Pathophysiology of backache
will be non-specific.6
The ageing process affects all aspects of the body,
The challenge for practitioners is to identify severe and the spine is not excluded. The lumbar spine forms a
spinal pathologies, the so-called red flags. These condi- protective canal around the conus medullaris down to
tions need proper investigation and often prompt inter- level L1/2 in adults, and then to peripheral nerve roots,
vention. each exiting the canal at appropriate levels.

The red flags of lumbar spinal As we age, the intervertebral disc loses height. This, in
turn, can cause hypertrophy of the facet joints and liga-
pathologies mentum flavum, and osteophyte formation. This process
potentially can cause instability of the lumbar column
In 2016, Verhagen et al published a review of the use of and compression of the nerve roots.
red flags in identifying serious spinal pathologies.6 It includ-
ed 16 guidelines from 15 countries in Europe, and despite It is important to emphasise that ageing is normal,
variance in the description of these warning signs and and the abovementioned processes affect all people
symptoms, they all pointed to the following pathologies: in variable degrees. This is visible on routine x-rays as os-
teophytes, disc-height loss and even spondylolisthesis
Malignancy which can be associated with musculoskeletal pain as
would be experienced in other joints. Consequently, the
Constitutional symptoms should alert the practitioner to red flag of age-inappropriate pain exists (pain under
potential malignant processes. Symptoms such as night the age of 20, and over the age of 70).
pain, fever and an elevated erythrocyte sedimentation
rate (ESR) could point to both malignancy and an What is normal?
infective process. The most common red flags for
malignancy were: This question poses a difficult challenge for the practi-
• unexplained or unintentional weight loss tioner, especially when the patient's expectations are
• history of cancer
• thoracic pain HANDBOOK OF GENERAL MEDICINE VOL 1

184 TREATMENT APPROACHES

extremely unrealistic, given his or her age. We are all positive test is pain experienced in the dermatome (not
timeless and limitless in our minds. lower back) and suggests a trapped nerve. Hip flexion
over 60 degrees causes stretching of the hamstrings
The effect of age on the spine is particularly important and discomfort, and seldom will be relevant beyond
when interpreting imaging modalities. Disc height will that degree of flexion.
be decreased with age, osteophytes will be visible, and
numerous radiological terms will be present, the older This will provide necessary information regarding
we get. backache and radiculopathy (root pain).

It is not uncommon in spinal specialist practices to Red flags must be interrogated and clinically investi-
receive referrals simply stating backache and then an gated for, and the common mimickers must actively be
elaborate radiological report of an age-appropriate excluded.
spine.
Spasticity, hyperreflexia and clonus should be as-
Assessment of the patient sessed and point to upper motor neuron pathology
which will be related to a conscious level and involves
History the spinal cord (L1/2 and upwards).
The doctor needs a detailed patient history regarding
onset, duration, nature, distribution, referral, factors im- Common mimickers
proving and aggravating pain and previous history of
similar epi­sodes. Take care to listen to potential contrib- Due to the common nature of backache, the mimick-
uting factors, such as social challenges, work-related ers are easily overlooked unless the clinician specifically
concerns or general stress-inducing factors. pays attention to them:

Examination The hip
This starts by observing the gait of the patient. Ask the Typical hip pain refers to the groin and down the lat-
patient to walk on their toes and heels. This provides eral aspect of the leg, generally not past the knee. The
significant information regarding strength in dorsi- and examination includes flexion, abduction and internal ro-
plantar flexion of the feet. The lower back must be ob- tation of the hip that should mimic the pain. A patient
served for previous surgeries, obvious deformity and with spine pathology hardly ever uses a crutch (unlike
range of motion which can be assessed by asking the hip pathology).
patient to bend forward (if pain allows).
Examine for trochanteric bursitis over the greater tro-
Direct palpation must involve the spinous processes, chanter. This can be treated with an injection of a local
the paraspinal muscles and particularly the iliac crest at anaesthetic and a steroid, to the great relief of the patient.
level L4/5 where iliolumbar ligaments implant and which
can be a significant source of focal pain. Vascular claudication
Vascular claudication presents similarly to neurogenic
The lower limbs should be examined under three mo- claudication with exercise intolerance of the lower
dalities: motor, sensation and reflexes. limbs and trophic changes. The history can be construc-
tive. Classically, the neurogenic claudication patient
The motor examination can climb up many flights of stairs, but not down, as re-
The motor examination should be focused on easy ac- lief occurs with flexion of the lower back. The vascularly
tions through the three joints of the lower limb (hip, knee, compromised patient struggles up the stairs due to exer-
ankle) and should include hip flexion (L2,L3), hip exten- cise intolerance, but not down. A routine spinal exami-
sion (L5/S1), knee flexion (L5/S1), knee extension (L3/L4), nation includes an examination of the pulses (femoral,
ankle dorsiflexion (L4/L5) and ankle plantar flexion (S1/ popliteal, posterior tibialis and dorsalis pedis), compar-
S2). Big toe extension (extensor hallucis longus) is L5 ex- ing left to right.
clusively and is handy as L5 is one of the most common
trapped roots of the lumbar spine. Meralgia paraesthetica
This condition presents with a decreased, sometimes
Sensation painful, sensory abnormality on the lateral aspect of the
Sensory examination should involve the dermatomes of thigh not beyond the knee due to entrapment of the
the lower limbs. The history often points to a specific der- lateral cutaneous nerve of the thigh just medial to the
matome already. Peri-anal sensation and rectal tone lateral implant of the inguinal ligament. Treatment in-
must be assessed if cauda equina syndrome is suspected. cludes weight loss, wearing loose undergarments and,
in persistent cases, surgical release.
Reflexes
Reflexes include the knee reflex (L3/L4) and ankle reflex Femoral hernia
(S1/2). Decreased reflexes are common in older people, This can present as pain or sensory loss in the L2,3 and
thus a comparison between left and right is important. 4 distribution, with weakness and even atrophy of the
quadriceps muscle group. The examination must in-
The straight-leg-raise test should be performed. Ask clude inguinal and femoral hernia exclusion.
the patient to lie flat, then lift the extended lower limb
one at a time off the ground under your strength. A

HANDBOOK OF GENERAL MEDICINE VOL 1

Anees Fayers, Nompumelelo Mokoena, Delcine Pillai, 31 years, Erica Thompson, Kgomotso Sechelo,
35 years, 25 years, Regulatory Affairs 65 years, 28 years,
Sales Manager, Mother, Associate, Theatre Nurse, Sales Representative,
Gauteng Gauteng Gauteng Gauteng Gauteng

Low back pain Dental pain Headaches & Eye surgery Dysmenorrhoea
low back pain

WHEN LIFE CAN’T WAIT...

LOW BACK PAIN | HEADACHE | STRAINS & SPRAINS | INFLUENZA PAIN
DENTAL PAIN | DYSMENORRHOEA | ADULTS & PAEDIATRICS†1,2

IN A RECENT SURVEY OF 227 SOUTH AFRICAN CONSUMERS:*3

92% of 196 Myprodol users agreed that Myprodol®
provides excellent quality analgesia

89% of 196 Myprodol users agreed that Myprodol®
is most effective at relieving pain

90% of 196 Myprodol users agreed that Myprodol®
is a brand they trust

Original. Dependable. Since 1987.1

†Myprodol is indicated for the relief of mild to moderate pain of inflammatory origin with or without fever. §IMS Apr 2018, N2B non-narcotic analgesics. ‡IMS Apr 2018, N2B1 non-narcotic analgesics.
*Pain Medication Consumer Market Assessment of 227 consumers; March 2018.3
REFERENCES: 1. Myprodol® Capsules approved package insert, May 1987. 2. Myprodol® Suspension approved package insert, June 1994. 3. Pain Medication Consumer Market Assessment, March 2018.

MYPRODOL® Capsules. Each capsule contains codeine phosphate 10 mg; ibuprofen 200 mg; paracetamol 250 mg. Reg. No. T/2.8/244. MYPRODOL® Suspension. Each 10 ml contains codeine phosphate
10 mg; ibuprofen 200 mg; paracetamol 250 mg. Reg. No. Y/2.8/119. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 201807301091049. Adcock Ingram
limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Tel. +27 11 635 0000. www.adcock.com.

186 TREATMENT APPROACHES

Aortic aneurysm servative modalities in acute and chronic backache,
This can present as acute lower backache. The exami- Van Tulder et al concluded that substantial evidence
nation must include the presence of pulses and an ab- exists to support the use of NSAIDs and muscle relax-
dominal examination to feel for a pulsating mass. Clini- ants which help manage pain intensity.9 Opioid usage is
cal suspicion needs to prompt further investigation. cautioned against as it carries addiction risks, specifical-
ly in the presence of social and behavioural problems.
Urinary tract infection/pelvic pathology Short, controlled courses are appropriate.
A urinary tract infection can cause both bladder symp-
toms and significant lower pelvic and even back dis- Bed rest as a modality has been proven to be inef-
comfort. A urinary dipstick should be able to prove a fective.9
symptomatic infection.
Initial conservative care should include a course of
Iliolumbar ligament pain NSAIDs and muscle relaxants. Coupled with physiother-
This presents as focal pain along the posterior iliac crest apy and other relaxation techniques, most bouts of
at level L4/L5. It is an incredibly tender spot paramed- pain will resolve within six weeks.
ian and can successfully be managed by infiltration of
the implant area with a local anaesthetic and steroid Important is re-assurance, education of the patient
combination. and a call for patience as, in a fast-paced world, pa-
tients seek quick solutions which are seldom possible
Imaging in lower backache with a backache.

The common modalities available are AP and lateral Obesity is a co-factor in persistent backache. A target
images of the lumbar spine, with the addition of flexion- of 10 % weight loss will demonstrate the commitment of
extension views if deemed necessary. This is generally the patient and lead to symptom improvement.
followed by MR-imaging.
Psychological and social assessment
In a meta-analysis and systemic review of imaging
strategies in lower backache, Chou et al concluded The Global Spine Care Initiative rightly emphasises the
that clinical outcome did not improve and that clini- evaluation of psychological and social assessment.8
cians should avoid immediate routine imaging in acute These factors, which include judgements, beliefs about
or sub-acute episodes of lower backache not accom- pain, emotional responses, underlying depression and
panied by red flags.7 particularly the effect of the workplace and social envi-
ronment on the individual, are challenging to manage.
A review of 5 365 requested outpatient lumbar MRIs,6 Accurate identification of these co-factors and open
reported only 13 % leading to a diagnosis of new cancer discussions and reassurance form the mainstay of treat-
or infection or planning for intervention. The guidelines ment. Psychosocial and psychological therapies form
used to request these studies included the red flags, an essential support structure for these problems.
but also prolonged periods of backache. All requests
in this study were deemed appropriate. This highlights When to refer?
the challenge with the red-flag backache that is not re-
sponding to conservative care as it cannot be ignored, Appropriate specialist referral should take place when
but is most likely significantly affected by social, behav- a red flag is identified.
ioural and psychological factors.
In the presence of psychological concerns and
CT-imaging with myelography is only used where MRI stressors, psychological and psychiatric help should be
is contra-indicated. sought.

Conservative treatment of backache References

In 2018, Haldeman et al8 published a series of articles 1. Spencer LJ, et al. Global, regional, and national incidence, preva-
grouped under The Global Spine Care Initiative. This lence, and years lived with disability for 310 diseases and injuries,
body of work summarises not only the challenges faced 1990-2015: A systematic analysis for the Global Burden of Disease
in managing lower backache, but also provides de- Study 2015. Lancet. 2016;388:1545-602.
tailed care algorithms for assessing and managing this
challenging problem. This can freely be accesssed at 2. Hoy DG, et al. Reflecting on the global burden of musculoskeletal
www.worldspinecare.org. conditions: Lessons learnt from the global burden of disease 2010
study and the next steps forward. Ann Rheum Dis. 2015;74:4-7.
The approach includes a strong emphasis on educa-
tion and self-care.8 The same accounts for manipulation 3. Da C Menezes Costa L, et al. The prognosis of acute and persistent
therapies, which include physiotherapy, manipulation low-back pain: A meta-analysis. CMAJ. 2012;184:E613-24.
techniques and mind-body treatment modalities such
as yoga and tai-chi, amongst others.8 4. Da Silva T, et al. Risk of recurrence of low back pain: A systematic
review. J Orthop Sports Phys Ther. 2017;47:305-13.
Commonly prescribed drugs include nonsteroidal
anti-inflammatory drugs (NSAIDs), opioid-based anal- 5. Foster N, et al. Prevention and treatment of low back pain: Evidence,
gesics, muscle relaxants and antidepressants. challenges, and promising directions. Lancet. 2018;391:2368-83.

In a systemic review to assess the efficacy of con- 6. Verhagen P, et al. Red flags presented in current low back pain
guidelines: A review. Eur Spine J. 2016;25:2788-2802
HANDBOOK OF GENERAL MEDICINE VOL 1
7. Chou R, et al. Imaging strategies for low-back pain: Systematic re-
view and meta-analysis. Lancet. 2009;373:463-72

8. Haldeman S, et al. The Global Spine Care Initiative: Care pathway
for people with spine-related concerns. European Spine Journal.
2018;27(Suppl 6):S901-S914

9. Van Tulder, et al. Conservative treatment of acute and chronic
nonspecific low back pain – a systematic review of randomized
controlled trials of the most common interventions. Spine.
1997;22(18):2128-56

TREATMENT APPROACHES 187

Decreasing eyesight in the elderly patient Treatment approaches

J van Soelen transparent and flexible; the tissues in the lens break
down and clump together, causing clouding of vision
MBChB, FCS Ophth (SA) (see Figure 1).

Ophthalmologist, Signature Eye Clinics, John Hill Eye Figure 1. Cataract of the lens
and Laser Centre, Cape Town
According to the World Health Organization (WHO),
There are multiple causes of decreasing eyesight in the cataracts are the leading cause of blindness and visual
elderly. With the deterioration of vision, elderly patients impairment in the world – 17 million of a total of 37 mil-
understandably become anxious and fearful of losing lion (47.9%).1 The overall prevalence of visual loss due to
their independence and financial security. It is impor- cataracts increases each year as the world population
tant not to be dismissive of any visual symptoms as the ages. It is predicted that in 2020 40 million people in the
majority of causes of visual loss in the elderly is treatable. world will be blind because of cataracts.2 They are the
Furthermore, maintaining optimum vision is important for cause of 30-50% of blindness in most African and Asian
mobility, preventing accidental falls and social isolation. countries. Cataracts occur at a younger age in rural ar-
Age is never a contra-indication for treating ophthal- eas and developing countries, presumably because of
mological disease. poor nutrition. Blindness due to cataracts is reversible.

When seeing an elderly patient with a complaint of a As most cataracts develop slowly, vision is not dis-
decrease in vision, it is important to find out the follow- turbed initially. Eventually, as the cataracts develop,
ing: seeing through the cloudy lenses becomes like looking
• Was the onset sudden or gradual? through frosted glass or mist. Initially, cataracts make it
• Are there any associated visual- and/or or other symp- more difficult to see small print or subtitles when watch-
ing television. Later on, distance vision becomes blurred,
toms, such as floaters, flashing lights or headaches? reading and driving become more difficult, colours ap-
• Is there any abnormal ocular appearance, such as pear muted, glare in bright lights sets in, and people
can see double with the eye that has the cataract.
redness of one or both eyes? Over time, patients develop difficulty in doing all their
• Is there any known underlying systemic condition, daily tasks.

such as systemic hypertension or diabetes; or do the When this occurs in an elderly patient, the individual
visual symptoms constitute the first symptom of a so relies heavily on the help of others to perform daily tasks.
far unknown systemic condition? As in the case of age-related macular degeneration,
this places a high burden on family members. When
Causes of a sudden decrease in vision in the elderly in- many people with cataracts do not have access to cat-
clude: aract surgery, together with an increase in the age of
• “Wet”/exudative age-related macular degenera- the population, there will be a corresponding increase
in demand for the society as a whole to help care for
tion (AMD) elderly patients whose vision is reduced by cataracts.
• Vascular occlusions (venous or arterial)
• Retinal detachment Old age per se is a risk factor for developing cataracts.
• Transient ischaemic attacks (TIA) or temporal arteritis, When people reach the age of 80 years of age, most

causing sudden momentary visual loss HANDBOOK OF GENERAL MEDICINE VOL 1

Gradual visual loss in the elderly can be due to:
• Cataract formation
• Glaucoma
• “Dry”/atrophic AMD
• Diabetic retinopathy and/or maculopathy
• Masquerading syndromes
• Tuberculosis of the eye
• Opportunistic infections associated with AIDS

The three most common causes of decreased vision
in the elderly are cataracts, glaucoma and AMD (wet
and dry). This article discusses these conditions in more
detail.

Cataracts

A cataract is clouding of the normally clear lens of the
eyes, causing vision to become blurred. The lens is po-
sitioned behind the coloured iris. It focuses light rays on
the retina. With ageing, the lens becomes thicker, less

188 TREATMENT APPROACHES

would have already developed cataracts or will be used for reading and discriminating detail, such as rec-
about to. Other causes are genetic factors, diabetes, ognising faces. The features of a healthy ocular fundus
the presence of intra-ocular inflammation and the use of are shown in Figure 2A.
steroid medication over some time, either as tablets, eye
drops or ointment applied around the eye area. Within an age range of 45-85 years, the global preva-
lence of any AMD, early AMD, and late AMD was 8.7%,
With early cataract formation, using glasses or chang- 8.0% and 0.4% respectively. The number of individuals
ing the prescription of glasses for both distance and with AMD globally was estimated in 2015 to be 196 mil-
near, may initially improve vision as cataracts alter the lion in 2020 and 288 million in 2040. Early AMD is more
refractive function of the lens. Once cataracts become common in individuals of European ancestry (11.2%)
too dense, however, the only treatment option is surgi- than in Asians (6.8%), whereas the prevalence of late
cal removal and replacing the natural lens with an im- AMD did not differ significantly. AMD of any type was
plant. less common in individuals of African ancestry. The in-
cidence of AMD steadily increases with age, affecting
Cataract surgery is the most common surgical proce- 2% of the population at age 40 and 25% of people by
dure, and one of the most successful operations per- age 80.
formed worldwide. Surgery is done under local anaes-
thesia and takes between 10 and 20 minutes. Implants The two forms of AMD, wet and dry, are classified ac-
can be monofocal, only correcting either distance or cording to the presence or absence of blood vessels
near vision, necessitating glasses to be worn for near or that have disruptively invaded the retina, respectively.
distance vision. Bifocal implants are also available, or
one eye can be corrected for distance, while the other Wet AMD
eye can be put in focus for reading distance (called
monovision), thereby doing away with the need to Wet AMD affects around 10-15% of all individuals with
wear any glasses. As any surgical procedure carries risks, AMD, but accounts for approximately 90% of all cases
there is no guarantee that any cataract procedure will of severe vision loss due to AMD. It is caused by the
be without complications. The most serious complica- growth of vessels from the choroid into or below the ret-
tion, namely an infection inside the eye called endoph- ina. These immature blood vessels leak fluid and blood
thalmitis, is rare, but can damage vision irreversibly. For (see Figure 2C) which ultimately become organised,
that reason, patients are advised to proceed with cata- leading to scar formation in the centre of the retina.
ract surgery only once it is ruled out that glasses can-
not improve vision adequately and that the symptoms Diagnosis is made by taking a history, assessing visual
have become more severe than the possibility of any acuity, and performing slitlamp biomicroscopy of the
complications. retinal fundus. Diagnosis is confirmed by obtaining an
ocular coherence tomography (OCT) – a high-defini-
When seeing an elderly patient with a gradual onset tion image of the 10 layers of the retina, the underlying
of decreased vision in one or both eyes without pain retinal pigment epithelium and the choroid and the
or redness, the patient should be advised to consult an vascular layer outside of the retina. Various abnormali-
optometrist. The optometrist will determine whether the ties lead to typical OCT images. Further clinical informa-
patient will benefit from a new prescription for glasses or tion can be obtained, if necessary, by capturing photo-
if the patient needs cataract surgery. graphs of the retinal fundus after injection of dye in the
peripheral circulation (hand or arm), using a specially
Age-related macular degeneration adapted camera.

Progressive dysfunction of the central retina due to An elderly patient too frail to sit at a slitlamp or cam-
macular degeneration is the leading cause of visual era for assessment poses a diagnostic dilemma as the
dysfunction in elderly patients in industrialised societies.3 retinal fundal image obtained with an indirect ophthal-
Globally, it was the third most common cause of severe moscope provides less detail of the fundus and neces-
visual impairment in 2015.4 The macula is the central sitates clinical acumen and experience to make the
area in the retina specialised for high visual acuity. It is correct diagnosis.

Symptoms of wet AMD include sudden onset of distor-

Figure 2. The ocular fundus – normal (A), dry AMD (B) and wet AMD (C)
HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 189

tion or deterioration of central vision and difficulty with read should be seen by an ophthalmologist within 24-48 Treatment approaches
reading. Refer any elderly patient presenting with these hours to rule out AMD and in particular wet AMD. If wet
symptoms immediately as vision deteriorates rapidly in AMD is present, treatment with intra-ocular antiVEGF
wet AMD. When left untreated, patients become una- agents should start as soon as possible after presenta-
ble to read or deal with their mail and financial matters, tion to stop the deterioration of vision and hopefully to
do not recognise faces, and cannot watch TV, drive, do restore vision to a degree, which can be achieved with
their shopping and cook. Consequently, they become treatment initiated within one to two weeks of onset of
dependent on others to help with daily tasks. Often, symptoms.
they are unable to continue their hobbies. The loss of
independence frequently leads to the onset of depres- Glaucoma
sion. Patients with this condition never become blind as
peripheral vision remains unaffected by AMD. The fur- Glaucoma is a group of diseases leading to the dam-
ther away the object, the more of the image they will age of the retinal ganglion cells and axons, resulting in
be able to make out. thinning of the optic nerve fibre layer and damage of
the optic nerve with optic disc-cupping (see Figure 3).
Wet AMD therapy focuses on blocking the growth of If glaucoma is left untreated, it invariably leads to blind-
blood vessels from the choroid. Treatment consists of in- ness. It is the most common cause of irreversible blind-
jections of anti-vascular endothelial growth factor (anti- ness worldwide, and preventable.
VEGF) into the vitreous cavity of the eyes every four to
eight weeks, using a sterile technique. Treatment may Figure 3. Damage of the optic nerve with optic
have to be continued for two to three years. disc-cupping, worse on the left

The most commonly used drug, bevacizumab – mar- Primary open-angle glaucoma (POAG,) is responsible
keted as Avastin® – was initially developed for intra- for 12.3% of blindness worldwide.6 In people above the
venous use in colorectal cancer. 5 The high cost of treat- age of 40, the prevalence of POAG is 1.9%. In one form
ment, as well as the need for frequent treatments over of glaucoma, the intra-ocular pressures (IOP) are within
several years, imposes a significant financial burden. normal limits. Called normal tension glaucoma (NTG), it
is common in elderly patients and rapidly progresses to
Visual aids to improve near vision to enable reading visual loss.
are available. Magnifying glasses are the mainstay, but
unfortunately, due to the high magnification needed, POAG prevalence is estimated to be highest among
reading is much more difficult and slow. The conse- Chinese people, intermediate in the Japanese, and
quent reduction in depth of focus often causes dizziness lower in Europeans and Indians. In a rural East African
and nausea while reading, so many patients do not find population-based study, POAG was found in 3.1% of the
any benefit in using magnifiers. Good lighting on read- population,7 and this high incidence occurs in African-
ing material is vital and can be separate or built into American patients worldwide.
magnifiers.
In most cases, glaucoma presents without any symp-
Dry AMD toms or pain except until very late when patients are
hampered by visual field loss. There is an underlying ge-
In dry or atrophic AMD, there are degenerative chang- netic predisposition in all cases of primary glaucoma,
es of the retinal photoreceptors and underlying retinal but not in secondary instances to intra-ocular inflamma-
pigment epithelium in the macula, resulting in atrophy tion or trauma. Family members of a patient with POAG
(see Figure 2B). The condition is much more common should, therefore, have regular assessments to rule out
than wet AMD, making up 85-90% of all AMD. The on- glaucoma. Patients screened for glaucoma by optom-
set of symptoms is slow, and can sometimes lead to etrists should have visual acuity, IOP, optic disc assess-
severe visual impairment. Symptoms are the same as ment and visual fields annually or at presentation. Oph-
for wet AMD in that there is a decrease in visual acuity, thalmologists will also measure the corneal thickness (it
and in the late stage, an inability to read and recog- affects IOP), assess the drainage angle of the eye and
nise faces. Distortion can also occur if the edge of the obtain optic disc-imaging.
atrophic area is near or under the fovea, the centre of
the macula. Dry AMD also eventually negatively affects As people above the age of 70 have a three to eight
the independence of elderly patients. To date, there is times higher prevalence of POAG, the whole glaucoma
no treatment that slows down the progression of the dis-
ease, and consequently it increases the burden to the HANDBOOK OF GENERAL MEDICINE VOL 1
patients and their families.

Since AMD patients typically develop the dry form
first, wet AMD occurs on a background of dry AMD; as
such, dry AMD can be considered a risk factor or even
precursor state for wet AMD. Significant overlap exists
in the underlying mechanisms of dry and wet AMD. In
spite of that, treatment of wet AMD does not prevent
deterioration of dry AMD in the same eye.

Any patient presenting with sudden deterioration of
vision, sudden onset of distortion or sudden inability to

190 TREATMENT APPROACHES

is another important cause of visual loss in the elderly.
With advanced disease, the patient has a microscopic
residual field of vision, which ultimately will be lost en-
tirely if no treatment is received.

Treatment of glaucoma is mostly with the daily ad-
ministering of drops to lower IOP. Since drops are very
effective owing to improved newer products on the
market, laser treatment or surgery is needed much less
frequently today than in the past. Treatment has to be
continued for life. Elderly patients may have difficulty to
administer drops or remember to do so, and will need
help from family or friends.

Visual acuity, IOP measurement, assessment of optic
disc-cupping and visual field assessment are needed
regularly to ensure the disease is optimally controlled,
and there is no further visual loss. Follow-up once stable
is usually once or twice a year.

References

1. Oduntan AO. Prevalence and causes of low vision and blindness
worldwide. S Afr Optom. 2005;64:44-54.

2. Foster A. Vision 2020: The cataract challenge. Community Eye
Health. 2000. 13:17-19.

3. Ambati J, Fowler BJ. Mechanisms of age-related macular degen-
eration. Neuron. 2012:75(1):26-39

4. Jonas JB, Cheung CMG, Panda-Jonas S. Updates on the epidemi-
ology of age-related macular degeneration. Asia Pac J Ophthal-
mol. 2017:6(6):493-497.

5. Karmel, M. Avastin new hopes and hesitations. Eyenet Magazine
2010:1:35-39

6. Quigley HA, Broman AT. The number of people with glaucoma
worldwide in 2010 and 2020. Br J Ophthalmol. 2006:90:262-267.

7. Buhrmann RR, Quigley HA, Barron Y et al. Prevalence of glauco-
ma in a rural East African population. Invest Ophthalmol Vis Sci.
2000:41:40-48

HANDBOOK OF GENERAL MEDICINE VOL 1

TREATMENT APPROACHES 191

An overview of glaucoma Treatment approaches

H Abrahamse-Pillay The proportion of people who are bilaterally blind
from glaucoma ranged from 9,5% to 33%. Between 41%
MBChB (UCT), FC Ophth (SA), MMed Ophth (Wits) and 58% were blind in one eye. Primary open-angled
glaucoma is the most prevalent form and is predicted
Specialist Ophthalmologist, Division of Ophthalmology, to affect 80 million people worldwide by 2020.4 The
Stellenbosch University, Stellenbosch black populations of the Caribbean, Africa and the USA
have the highest prevalence of open-angle glaucoma.
Glaucoma is a group of pathological disorders that Even within this group, there are differences in preva-
causes a progressive, often bilateral, optic neuropathy lence, depending on genetics, environmental factors
that is associated with characteristic structural damage and socio-economic factors. Glaucoma has an ear-
of the optic nerve and has associated visual dysfunc- lier onset in black populations with a more aggressive
tion, including visual field loss.1 Raised intra-ocular pres- clinical course. According to Dr John Salmon (Oxford
sure is one of the main risk factors, but its absence does Eye Hospital, England), the coloured population in the
not exclude disease. Functional damage is also taken Western Cape has a high prevalence of angle-closure
into consideration, but again does not form part of the glaucoma (PhD thesis 1993, UCT – Primary Angle Clo-
definition of glaucoma. Glaucoma can be congenital, sure Glaucoma in Cape People of Mixed Ethnic Back-
primary or acquired and can have ocular or systemic ground with Special Emphasis on Chronic Angle-Closure
associations (see Figure 1). Glaucoma). This is traditionally seen in Asian and Indian
populations.
Classification of glaucoma
(gonioscopically)2,3 Impact on society

There are different ways to classify glaucoma based People with bilateral visual field loss from glaucoma
on the anatomical, gonioscopic-angle-evaluation, bio- have worse self-reported visual abilities and worse per-
chemical, molecular and genetic views. Each has its formance of tasks. Lighting was highlighted as the most
benefits. Here, the gonioscopic classification is used. common complaint when a person has glaucomatous
Employing the traditional method of defining whether damage, followed by walking and balance. The loss of
the angle is open or closed has implications for the dif- confidence while walking leads to a decrease in overall
ferent treatment options available. quality of life and an increase in morbidity and mortality.
Difficulty with reading and near-vision tasks, as well as
The three primary alphanumeric systems that are cur- with driving, were frequent complaints. These patients
rently used for grading the angle are those of Scheie, also reported an increased incidence of anxiety and
Shaffer, and Spaeth. The Shaffer classification is the worry about blindness.5 These complaints can be divid-
most commonly used. The Scheie classification uses Ro- ed into five factors.
man numerals, and the angles are graded inversely.
The Spaeth classification uses all the available informa- 1. Near vision
tion to offer a more comprehensive classification. 2. Peripheral vision
3. Dark adaptation and glare
Shaffer 4. Personal care and household tasks
Grade 4 (35-450): ciliary body visible 5. Outdoor mobility
Grade 3 (25-350): scleral spur visible The above five factors correlated well to the loss of
Grade 2 (200): trabecular meshwork visible visual field, as well as mean deviation measures on a
Grade 1 (100): Schwalbe’s line visible Humphreys visual field test. These were used in the devel-
Grade 0 (00): iridocorneal touch opment of a Glaucoma Quality of Life 15 question ques-
tionnaire.6 The aim of developing a glaucoma specific
Prevalence quality-of-life evaluation questionnaire is to determine
the key measure of success with adequate treatment.
Glaucoma is the second leading cause of blindness In resource-poor settings, another individual will often
worldwide, accounting for 15% of blindness in Africa have to look after the blind relative and therefore can-
(8% of the 39 million blind population worldwide).4 Ac- not be economically active or receive an education.
cording to studies conducted in sub-Saharan Africa, This has a knock-on effect in terms of access to health-
including South Africa, the prevalence of all types of care and treatment compliance, with less than optimal
glaucoma ranges from 4,5% to 5,3%. Open-angle glau- diagnosis and management. Owing to poor awareness
coma is six times more prevalent than closed-angle and socio-economic hardships, patients present late
glaucoma in the same population set, except in those and have poor outcomes.4
of mixed South East Asian and western European origins
who have an almost twofold presence of closed-angle HANDBOOK OF GENERAL MEDICINE VOL 1
glaucoma, compared to open-angle glaucoma.

192 TREATMENT APPROACHES

Open-angle glaucoma Primary Primary open-angle glaucoma
Normal tension glaucoma
GLAUCOMATOUS OPTIC Secondary Axenfield Rieger's syndrome
NEUROPATHY Juvenile open-angle glaucoma Peter's anomaly
Primary Ocular hypertension Aniridia
Congenital glaucoma Associated with other Glaucoma suspect Sturge Weber
Pigmentary glaucoma
anomalies Phacolytic glaucoma Neurofibromatosis
Secondary glaucomas
Closed-angle glaucoma Steroid-induced glaucoma
Primary Exfoliative glaucoma
Figure 1. Classification of glaucoma
HANDBOOK OF GENERAL MEDICINE VOL 1 Secondary Angle-recession glaucoma
Ocular

Systemic
Aphakicglaucoma
Primary-angle closure with

pupil block
Acute angle-closure glaucoma

Subacute angle-closure
glaucoma

Chronic angle-closure glaucoma
Plateau iris syndrome

Secondary-angle closure with
pupil block

Secondary-angle closure
without pupil block