rheumatology

1. RHEUMATOLOGICAL
MANIFESTATIONS IN HIV
ADENITAN A.M

2. Outline
• Introduction
• Epidemiology
• Etiopathogenesis
• Manifestations
• Conclusion
• References

3. Introduction
• Since the beginning of the epidemic in the late 80’s, more than
70million people have been infected with the Human
Immunodeficiency Virus (HIV) and about halve of this people
die of the disease. Globally, 36.7million people were living with
HIV at the end of 2016. An estimated 0.8% adults age 15-49yrs
are living with the disease worldwide. Sub Saharan Africa
remain the most severely affected with nearly 1 in every 25
adults(4.2%) living with HIV and accounting for nearly 2/3 of
the people living with the disease worldwide.

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• The global epidemic of HIV infection has affected the practice of
almost every clinician, and rheumatologists are no exception.
Earliest reports of rheumatological associations of HIV infection
were published in mid-1980, and since then much interest has
been aroused in this topic.
• These conditions include arthralgia, painful articular syndrome,
Reiter’s syndrome, reactive arthritis, HIV-associated arthritis,
undifferentiated spondyloarthropathy, soft tissue rheumatism,
septic arthritis, avascular bone necrosis, osteomyelitis,
hypertrophic osteoarthropathy, myalgias like polymyositis,
dermatomyositis,

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• Sjogren’s like syndrome – Diffuse infiltrative lymphocytic
syndrome (DILS), vasculitis like Schonlein-Henoch purpura,
polyarteritis nodosa (PAN), giant cell arteritis(GCA), Wegener’s
granulomatosis (WG), Raynaud’s phenomenon and Behcet’s
syndrome. HIV-related neoplastic processes namely Kaposi’s
sarcoma and non-Hodgkin’s lymphoma can also affect the
musculoskeletal system.

6. Epidemiology
• The reported prevalence of articular manifestations of HIV
varies, but with sub-Saharan Africa accounting for almost 70%
of the people living with HIV, this results in a considerable
burden of disease in the region.
• Reiter’s syndrome was the first reported rheumatic disorder in
HIV infection. Before the widespread implementation of highly
active anti-retroviral therapy (HAART), retrospective studies
calculated the rates of musculoskeletal complications to be
between 11% to 72% .

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• In the HAART era, rheumatic complications declined
significantly but continue to be prevalent with even new
manifestations emerging.
• The prevalence and characteristics of the rheumatic and extra-
rheumatic manifestations of HIV infection determined in one of
the prospective studies suggested that out of 101 patients with
HIV infection, the musculoskeletal system was involved in 72
patients. Thirty five patients had arthralgias, 10 had Reiter’s
syndrome, 2 had psoriatic arthritis and myositis respectively,
and 1 had vasculitis.

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• A retrospective record review of 888 inpatients with HIV:
rheumatic manifestations were present in 80 (9%) with
arthritis/arthralgia 49 (5.5%), septic arthritis 9 (1%), and
osteomyelitis 8 (0.9%), connective tissue diseases (CTDs) 6
(0.7%) (SLE 3, rheumatoid arthritis 1, polymyositis 1, and
systemic sclerosis 1), avascular necrosis 6 (0.7%) (hips 3, knees
2, and shoulder 1). There were no cases of seronegative
spondyloarthritis or Sjögren’s ’s syndrome.
• In Nigeria, Adelowo et al reported five cases to illustrate the
spectrum of rheumatological manifestations of HIV among
Nigerians. In other parts of Africa and globally, available reports
are on the rate of positivity to HIV antibodies among patients

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Okwara et al in a study on predictors of articular disorders among
HIV-Infected patients, recruited 480 participants, both HIV +ve
subjects (HPS) and HIV –ve subjects (HNS) were made up of 95
males and 145 females.
There was statistically significant difference between the
frequency of occurrence of articular disorders among the HPS of
37.1% (89/240) and the HIV-negative controls of 16.2%
(39/240). Arthralgia frequency of 29.6% (71/240),
HIV-associated arthritis 4.6%, (11/240), Reiter’s disease 1.3%
(3/240), undifferentiated spondyloarthropathy 1.3%, (3/240) and
gout 0.4% (1/240) were seen among the HPS. Only arthralgia was
found among HNS.

10. Etiopathogenesis:
Rheumatological consequences of HIV infection
Events in HIV infection
Direct effect
Indirect effect
1. Chronic immune response to
HIV antigens: humoral and
cell mediated
Rheumatological
manifestations
• Arthritis, myositis and vasculitis
• B-cell hyperactivity, autoantibody
production-specific symptoms of
chronic immune stimulation
• Lymphocytic infiltrative syndromes
e.g., DIL
• Vasculitis
• Inflammatory myopathy

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Events in HIV infection
Indirect effect
2. Mediated by intact
components(CD8 cells) of
immune system
3. Selective immune
deficiency affecting CD4+
“helper” T-cells
Rheumatological
manifestations
• Reiter’s syndrome, psoriatic
arth and other undifferentiated
spondyloarthropathies
• Opportunistic infection of
musculoskeletal system
• Amelioration of CD4 dependent
Rheumatic diseases e.g. RA, SLE

12. Rheumatological Laboratory abnormalities
associated with HIV infection
• In HIV-infected patients, autoimmune phenomena is fostered
by a polyclonal stimulation of B cells, or the homeostatic
expansion of naive and antigen-experienced T cells after the
initiation of effective HAART.
• Laboratory abnormalities may consist of the presence of RF,
cold agglutinins or ANA . Anti-centromere ANA were observed
in up to 84% of individuals and circulating immune complexes
in up to 98%.C3 and C4 complement levels were mostly normal,
although in some subjects elevated or low levels were measured.

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• ANCAs (both c-ANCA and p-ANCA) are present in
approximately 43% by ELISA. Similarly, false positive results
for HIV antibody by ELISA/Western blot may be seen in SLE.
• Infections are a known trigger of aCL production. In HIV
infected patients, aPLs were found in up to 94% of the cases and
anti-2 glycoprotein I (GPI) antibodies in up to 47%. The lupus
anti-coagulant was mostly negative. The full picture of the APS
is uncommon, a fact which may be related to the relatively low
prevalence of anti-GPI antibodies and the observation that aCLs
are often transient and disappear with antiretroviral treatment.

14. Clinical presentation of rheumatological
manifestations in HIV patients
HIV-associated arthralgia
• Arthralgia is the most common but non-specific articular
complaint of HIV-positive patients (with a frequency reported
to be >45%). It tends to occur in the acute phase of the infection
and is the result of direct infection of the joint by the virus. The
frequently affected joints are the knees, shoulders and elbows. It
may manifest as a mono-, oligo- or polyarticular disease. It can
be transient or intermittent. Imaging features are normal. The
most appropriate treatment along with a non-narcotic analgesic
such as acetaminophen or tramadol, is reassurance.

15. Painful articular syndrome
• Painful articular syndrome is described less commonly than
arthralgia but is characterized by acute severe debilitating
pain of short duration lasting less than 24hrs. It has been
reported to occur in the late stages of HIV infection and
commonly affects the knees, shoulders and elbows. Clinically
there are no signs of synovitis. Imaging features may be
normal, but sometimes a joint effusion is noted. Peri-
articular osteopaenia may or may not be present. The exact
etiology is unclear, and treatment is symptomatic.

16. HIV-associated arthritis (HIVAA)
• HIVAA has been described more commonly in patients from
sub-Saharan Africa. It occurs at any stage of HIV infection
and most often presents as an asymmetric non erosive
oligoarthritis, more commonly in men. The lower limbs,
especially the knees, are most commonly affected and it is
described as self-limiting, lasting less than 6 weeks.
• A symmetrical polyarthritis pattern resembling rheumatoid
arthritis (RA) may also be seen. Deformities similar to RA are
described although the onset is more acute and less erosive.
A Jaccoud arthropathy may also form part of this spectrum.

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• Imaging findings similar to RA may be noted and includes peri-
articular osteopaenia, erosions and joint space narrowing.
Periostitis and proliferative new bone formation helps to
distinguish the condition from RA.
• Serological tests such as rheumatoid factor (RF) and anti-
nuclear factor antibodies associated with inflammatory
arthritides are negative, as is the HLA B27 genotype. They also
do not fulfil the criteria for the spondyloarthropathies.
• The treatment, includes NSAIDs, and in more severe cases, low
dose corticosteroids. Patients may respond equally well to HCQ
and sulphasalazine.

18. Spondyloarthropathies (SpA)
• The SpA have been reported as one of the commonest
manifestations of HIV infection and include reactive
arthritis/Reiter’s syndrome, psoriatic arthritis and
undifferentiated SpA. Studies among Caucasians have been
associated with a positive HLA B27 in 70 - 80% of patients while
the HLA B27 is usually not common in studies from Africa. The
joint manifestations may occur at any stage of the disease.
Treatment with antiretroviral therapy has been shown to
ameliorate the symptoms of SpA in many of the patients.

19. Reactive arthritis(ReA)/Reiter’s syndrome
• Reactive arthritis is more prevalent in HIV-positive paediatric
and adult cohorts, compared with HIV-ve population . It was
diagnosed in 0.4–10% of the HIV-infected subjects, most of
whom had asymmetric oligoarthritis.
• A preceding hx of urogenital or gastrointestinal infection in
frequently obtained .Enthesopathy is highly prevalent and
sacroileitis may occur. Among the extra-articular
manifestations, conjunctivitis, circinate balanitis, urethritis and
keratoderma blennorrhagicum are frequent . Extensive
psoriasiform skin manifestations have been described, these
may cause confusion with a diagnosis of psoriasis.

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• The synovial fluid white cell count rises to 2,000 -10,000/l,
synovial fluid cultures are negative, and the most common
microorganism present in the synovial membrane is Chlamydia.
Unlike HIVAA, HLA-B27 association exists in 70% - 90% of
patients.
• NSAIDs are the mainstay of treatment, indomethacin in
particular is recommended because of its additional property to
inhibit HIV replication, whereas rarely, phenylbutazone is
preferred in refractory cases. Sulphasalazine , MTX, HCQ can all
be used.

21. Psoriatic arthritis(PsA)
• PsA is almost universally associated with HIV infection. It
occurs most commonly in the late stage of HIV infection .The
psoriatic rash can be extensive – especially in patients not
receiving HAART. The arthritis is predominantly polyarticular,
involves lower limbs, and is progressive. The etiologic
mechanisms remain unclear, but most likely represent a
combination of genetic and environmental factors. The
associated arthritis has also been described as more destructive
and erosive, as well as more refractory to treatment.

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• HAART has been shown to be effective in treating both HIV
associated psoriasis and its associated arthritis. Phototherapy,
etretinate, and MTX can also be useful. Etanercept helps in
modulating the inflammatory activity and progression of the
disease

23. Undifferentiated spondyloarthropathies
• Patients who do not exhibit a full spectrum of clinical
manifestations that allow them to be classified as SpA are
labelled as undifferentiated spondyloarthropathy.
• Enthesitis, dactylitis, oligoarthritis, sacroiliitis, nail changes,
and conjunctivitis are commonly seen in such patients and they
are usually negative for RA factor, ANA, and HLA B27. The
pathogenesis of HIV-associated spondyloarthropathy (SpA) is
poorly understood.
• On magnetic resonance imaging and sonographic imaging,
inflamed knees, extensive polyenthesitis, and adjacent osteitis
are the frequent findings.

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• The arthritis deteriorates despite conventional anti-rheumatic
treatment, but improves dramatically after highly active
antiretroviral treatment, which is accompanied by a significant
rise in CD4 T-lymphocyte counts. Otherwise, treatment is
symptomatic (NSAIDs); intralesional corticosteroids and
sulphasalazine may be used in more extensive disease.

25. Septic arthritis
• HIV is a risk factor for septic arthritis ; septic tenosynovitis and
bursitis have been less often described. Although the joints are
the most common localization of septic complications in the
musculoskeletal system, these infections are only observed in
1% of HIV-infected individuals.
• There appears to be no clear association with CD4 counts. Some
studies, however, question whether HIV infection actually
predisposes for articular infections and suggest that the
predominant risk factor for septic arthritis in the HIV infected
population is represented by simultaneous intravenous drug
abuse.

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• Septic arthritis usually affects young men, with the large weight-
bearing joints of the lower extremities commonly involved. For
unclear reasons, the sternoclavicular joints are a preferred
target of infection in intravenous drug users. Pyogenic
organisms predominate at CD4 counts >250/l, whereas
opportunistic pathogens are observed when the CD4 counts are
<100/l . After the initiation of HAART, preexisting
opportunistic pathogens such as mycobacteria can become
symptomatic by immune reconstitution.
• Treatment involves arthrocentesis if there is collection, use of
antibiotics after culture and physiotherapy

27. Osteonecrosis (avascular necrosis)
• HIV-infected patients have an 100-fold elevated risk of
osteonecrosis. At the hip, which is the most frequent localization
of osteonecrosis, the prevalence was estimated as 4.4% by MRI .
The annual incidences were 0.7 and 0.3% with regard to
asymptomatic and symptomatic osteonecrosis of the femoral
head.
• Some of the factors which might be expected to contribute are
the use of corticosteroids, HIV-related vasculitis, protein S
deficiency, antiphospholipid antibodies, antiretroviral therapy,
especially protease inhibitors and hyperlipidaemia. These
factors, together with alcohol abuse and severe
immunosuppression associated with HIV infection, have been

28. Hyperuricaemia and gout
• High frequencies of hyperuricaemia (up to 42%) have been
observed in HIV-infected individuals. In HIV patients, the
annual incidence of gout is 0.5%, an order of magnitude higher
than the incidence in the normal population.
• With uncontrolled HIV replication, serum urate elevation may
result from increased cell turnover. Aside from the HIV
infection itself, urate serum levels are also altered by
antiretrovirals especially didanosine and stavudine.
• Urate elevation may result from the mitochondrial toxicity of
these drugs, because mitochondrial damage increases the
formation of lactate, which stimulates urate reabsorption at the
proximal tubules of the kidney.

29. Articular complications of anti-retroviral
therapy
• Arthralgia, monarthritis, oligoarthritis and adhesive capsulitis
have been associated specifically with the use of indinavir.
Indinavir is a protease inhibitor (PI), which tends to form drug
crystals in the urogenital tract, giving rise to nephrolithiasis.
Indinavir crystals were not detected in the SF, however.
Indinavir is now rarely used in HAART for its unfavourable
pharmacokinetic profile, efficacy and side-effects. A prospective
survey suggested that joint pain may also be associated with
other PI (ritonavir and saquinavir).

30. Myopathy
• Skeletal muscle involvement can occur at all stages of HIV
infection, and may represent the first manifestation of the
disease. Myopathies in HIV-infected patients are classified as
follows:
 HIV-associated myopathy and related conditions, including HIV
polymyositis, inclusion-body myositis, nemaline myopathy, diffuse
infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome,
vasculitic processes, myasthenic syndromes, and chronic fatigue;
 Muscle complications of anti-retroviral therapy, including zidovudine
and toxic mitochondrial myopathy related to other nucleoside-analogue
reverse-transcriptase inhibitors (NRTIs), HIV-associated lipodystrophy
syndrome, and immune restoration syndrome related to highly active
antiretroviral therapy (HAART);

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Opportunistic infections and tumour infiltrations of skeletal muscle;
and
Rhabdomyolysis.
 Few other rare presentation includes dermatomyositis, fibromyalgia, and
osteomyelitis complicating pyomyositis.
Patients presenting with proximal muscle weakness can show a normal or minor
elevation of creatine phosphokinase (CPK), and normal findings on
electromyography. Whereas, muscle biopsy can reveal CD8 polymyositis. This
illustrates the importance of muscle biopsy in identifying the underlying pathology
in HIV infected patients with muscle weakness and little or no abnormality in
laboratory investigations.

32. Diffuse Infiltrative Lymphocytosis
syndrome (DILS)
• Diffuse infiltrative lymphocytic syndrome is a rare
manifestation of HIV which is characterised by a diffuse visceral
CD8 lymphocytic infiltration, a persistent CD8 lymphocytosis,
bilateral parotid swelling and cervical lymphadenopathy.
Definite DILS is found in 3% of the patients, and possible DILS
in 3.4%. The prevalence of definite DILS is significantly higher
in African Americans (4.5%). Epstein-Barr virus (EBV) and
HIV, but not CMV, where found in the pathogenesis of DILS,
these was suggested by the immunohistochemical findings.
Evidence is also there suggesting that CD8 lymphocytosis
represents an immune response to viral infection rather than a
malignant disorder, i.e., it is a benign monoclonal expansion.

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Comparison of clinical features of Sjogren syndrome and
HIV associated DILS. Features which are different
Sjogren syndrome
DILS
– Sex 90% female 90% male
– Lymphadenopathy Common Massive
– Extraglandular inv Uncommon Common
– Anti-Ro, Anti-La High titre, low titre
– HLA-DR HLA-DR2, DR3 HLA-DR5,
DR6
– Infiltrating lymphocyte CD4+ Mainly CD8

34. HIV-associated polymyositis
• This has been described in up to 2–7% of HIV-positive patients
and can be observed at any stage during the course of the
infection. In a prospective trial of consecutive HIV-infected
patients who are not on HAART but clinically suspected skeletal
myopathy or raised serum CK levels, one-third of the cases had
an inflammatory condition on skeletal muscle biopsy
(microvasculitis, myositis).
• The muscle is typically infiltrated by CD8 T-lymphocytes . Viral
antigen and nucleic acids have been detected in endomysial
lymphocytes.

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• HIV-associated polymyositis is clinically and histologically
indistinguishable from idiopathic polymyositis but mostly has a
good outcome as it responds well to immunosuppressive
therapy and may even resolve spontaneously. About half of the
patients simultaneously have a DILS

36. Zidovudine(ZVD) induced myopathy
• Zidovudine causes a myopathy by interfering with the
replication of mitochondrial DNA. The myopathy is probably
specific to ZVD because it is generally not observed under
treatment with other anti-retroviral nucleoside analogues .
Zidovudine myopathy is probably the most frequent muscle
complication in HIV patients and also more common than the
inherited mitochondrial myopathies due to mutations in the
mitochondrial genome. Patients experience muscle weakness
either under dynamic or static exercise.

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• The serum CK is often normal or only minimally elevated but
muscle histology reveals a high frequency of ragged-red fibres in
the Gomori Trichrome stain. Zidovudine myopathy may be
prevented by uridine supplementation and resolves within
months after drug cessation

38. Vasculitis
• The vasculitides associated with HIV are usually not life threatening,
and present as a single flare rather than a relapsing illness. A wide
spectrum with inflammatory diseases has been described in patients
with HIV infection. Lesions included in these are hypersensitivity
vasculitis, polyarteritis nodosa, and Henoch Schonlein purpura,
others being Kawasaki disease, giant cell arteritis, Wegener’s
granulomatosis, and isolated angiitis of central nervous system,
small-vessel vasculitis, and inflammatory lung disease.
• Cryoglobulins (types II and III) were found in 1–27% of HIV mono
infected, but far more frequently in HIV/HCV-co-infected patients.
Majority of these patients are asymptomatic for cryoglobuminemia.

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• Among the vasculitides affecting the medium-sized arteries,
cases of HIV-associated polyarteritis nodosa were observed.
HIV antigens and HIV RNA were observed in the vessels in the
absence of hepatitis B surface antigen. Behcet’s disease has also
been described sporadically in HIV-infected patients. Among
HIV-infected patients with stroke, vasculitis was identified as
the cause in 13% of individuals. Cerebral vasculitis can occur
immediately after HIV infection or in more advanced disease
with CD4 counts <200/l.
• Corticosteroids remain the mainstay of treatment, although
cytotoxic drugs also have been employed in refractory cases.

40. SLE and HIV
• SLE generally improves during the course of untreated HIV
infection, which is consistent with the importance of CD4 T cells
in the pathogenesis of SLE. Conversely, inactive preexisting SLE
can flare with immune recovery under HAART. Difficulties in
the differential diagnosis between SLE and HIV infection may
arise, because there are many clinical and laboratory
similarities. For example, oral ulcerations, sicca syndrome,
alopecia, arthritis, fever and neuropathies can be features of
both conditions. Similarly, both entities can be accompanied by
leucopenia, lymphopenia, thrombocypenia, hyper
gammaglobulinaemia, ANA and the presence of aPLs.

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• Anti-dsDNA antibodies, are considered by some but not all
investigators to be specific for SLE . Anti-HIV antibody tests can
be falsely positive in SLE because sera from SLE patients
contain antibodies that interact with HIV in western blot
analyses. Thus, positive HIV-antibody tests should be confirmed
by antigen or nucleic acid detection in the setting of a CTD. It
has also been described that the HIV infection emerged and
took a rapidly progressive course after immunosuppressive
therapy was initiated in order to treat SLE . For this reason, it
strongly recommended that subjects with SLE be tested for HIV
prior to the commencement of immunosuppressive treatment.

42. RA with HIV
• The effects of HIV infection on rheumatoid arthritis (RA) are a
matter of debate as there is no agreement on the influence of
HIV related immunodeficiency on this disease. Patients with RA
with symmetric joint erosions and positive rheumatoid factor
(RF) who develop classic acquired immunodeficiency syndrome
(AIDS) improve with resolution of bony erosions and
disappearance of RF.

43. Arthritis and HIV in Children
• Arthritis associated with HIV infection also occurs in children,
although it is reported less frequently than in adults. A series of
35 children with arthritis and HIV infection and 97 HIV
negative children with juvenile idiopathic arthritis was reported
from Durban. Arthritis was the presenting manifestation of HIV
infection in 78% of the children.

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• When compared with children with juvenile idiopathic arthritis,
the HIV-infected children showed a greater male to-female ratio
of 2.5:1, systemic-onset arthritis was not seen and
spondyloarthropathy features were present in 34% compared
with 5% for uninfected children. There was no difference in the
prevalence of patients with oligoarthritis and polyarthritis.

45. Immune reconstitution inflammatory
syndrome(IRIS)
• An IRIS with exacerbation of autoinflammatory or autoimmune
diseases can occur with the successful treatment of HIV with
antiretroviral therapy. Most autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus and
polymyositis occur de novo during IRIS, while in about 20% of
cases there is a flare of the disease which was quiescent during
the immunosuppression from HIV infection. Other organ-
specific autoimmune diseases which may manifest include
autoimmune thyroiditis and pulmonary sarcoidosis.

46. Anti-rheumatics in HIV-infected
individuals
• For symptomatic relief, NSAIDs can be used according to the
guidelines in HIV-negative patients. Interestingly,
indomethacin has been shown to inhibit HIV replication in
vitro, with the dose for 50% inhibition of viral replication
corresponding to 50 mg of indomethacin. Indomethacin may,
therefore, be the NSAID of choice in HIV patients. SSZ has been
used successfully in SpAs not sufficiently responding to NSAIDs
and does not adversely promote HIV replication.
• HCQ has been effectively used in HIV associated arthropathies.
Moreover, HCQ has anti-retroviral activity. In a dose of 800
mg/day, HCQ was equal to zidovudine in controlling viral
replication in HIV-infected patients.

47. Continue
• Methotrexate is also used with caution because of concern that
it can promote viral replication due to its immunosuppressive
properties. It has been used for inflammatory arthritis
depending on whether patients are on concomitant
antiretroviral therapy, the level of the CD4 count and the viral
load. There are no defined protocols for its use, and careful
monitoring is essential. Some patients with arthritis which is
refractory to conventional disease-modifying anti-rheumatic
drugs (DMARDs) have also been treated with anti-TNF agents
but these should be reserved for use by clinicians familiar with
their use and monitoring in this setting.

48. Conclusion
• Rheumatologists will encounter growing numbers of people
living with HIV as they live longer with the infection controlled
by HAART. Musculoskeletal symptoms are common, much of
which are explained as myalgia, arthralgia and soft tissue
rheumatism. However, a small proportion of patients will be
diagnosed with inflammatory rheumatic diseases requiring
careful balance of DMARDs and biologics with ART.
• Awareness regarding presence and interpretation of the
spectrum of auto-antibodies in these patients is important as
presence of auto-antibodies can lead to diagnostic dilemma.

49. continue
• Anti-viral effects of drugs like indomethacin and HCQ, and
impact of HAART in producing and affecting the clinical
spectrum of rheumatic disease has to be kept in mind while
treating HIV-infected patients.
• Early understanding and treatment of rheumatic diseases will
go a long way in reducing the physical, mental, social, and
economic burden created by the scourge of the disease in HIV-
infected patients.

50. Thanks for listening

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