Rheumatic Manifestations Of HIV Infections Biology Essay

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With increasing number of individuals getting HIV infection, the number of HIV-infected patients with rheumatic manifestations is bound to increase. HIV can present with myriad of presentations reactive arthritis, infective arthritis, diffuse infiltrative lymphocytic syndrome (DILS) and myositis are some of the rheumatological conditions that can occur in a HIV-infected individual. This review elaborates some of the more common rheumatic problems that are associated with HIV infection.

The aim of this communication is to give a brief review of the varied rheumatic manifestations that occur in the course of HIV infection with particular emphasis on the impact of antiretroviral therapy on the changing clinical spectrum. [3] 

HISTORICAL ASPECTS

Human immunodeficiency virus infection has been associated with protean clinical manifestations. The first report of association of HIV infection with reactive arthritis was published in 1987. [4] Since then a plethora of rheumatic manifestations have been reported since the late eighties. [5] , [6] , [7] , [8] , [9] , [10] , [11] .

INCIDENCE

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The exact prevalence of rheumatic manifestations is not known, it has been estimated that from retrospective analysis of patients with HIV infection rheumatologic features occur in 30-40% of HIV-infected patients. While in western literature, the prevalence of rheumatological complaints ranged from 10-45%. [12] , [13] In India the prevalence is low, upto 2-4% in most case series. The difference in prevalence could be due to different profile of presentation and sexual practices in developing countries like India as compared to the West. [14] , [15] , [16] .

In one of the prospective studies by Berman et al 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. Also found were 2 previously unreported syndromes. The first, occurring in 10 patients, consisted of severe intermittent pain involving less than four joints, without evidence of synovitis, of short duration (2-24 hours), and requiring therapy ranging from NSAIDs to narcotics. The second, occurring in 12 patients, consisted of arthritis (oligoarticular in 6 patients, monoarticular in 3 patients, and polyarticular in 3 patients) involving the lower extremities and lasting from 1 week to 6 months. [17] 

Another study comparing 74 consecutive HIV positive patients clinical and laboratory findings of rheumatic manifestations were compared with 72 control HIV negative subjects with similar risk factors for HIV, the study concluded that rheumatic manifestations were more frequently observed in the HIV positive group than the HIV negative group: arthralgias were found in 45%, arthritis in 10%, and Reiter's syndrome in 8% patients. [18] 

ETIOPATHOGENESIS

The rheumatic manifestations (Table 1) can be attributed either to the direct effect of HIV infection or to host immune response to the infection; those mediated by intact components of the immune system (CD8 cell), and those that arise because of immunodeficiency with genetic and environmental factors also contributing a key role.

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The rheumatic manifestations of HIV results from a complex interplay of various immunologic, environmental, and genetic factors in a background of HIV infection. A three cell model has been propagated in the causation of rheumatic manifestations. In this model a dendritic cell presents a peptide from an immunogenic protein to both a CD4 and CD8 T-cell clone. This interaction disrupts tolerance and results in the expansion of the cytotoxic T-cells resulting in various clinical rheumatic syndromes. [19] Human immunodeficiency virus itself may be implicated as a direct cause of arthritis variously termed as HIV associated arthropathy or AIDS arthritis as amplified by the fact that HIV has been isolated from synovial fluid. [20] A wide variety of systemic autoimmune rheumatic diseases are also associated with HIV infection. These include Sjögren's-like syndrome, inflammatory myopathy, and systemic vasculitis. It has been postulated that antibodies against the third hypervariable region (V3) of HIV-1 gp120 (V3-specific antibodies) might have a role in the autoimmune phenomena observed in HIV-infected persons. In fact v3 antibodies have been detected from patients suffering from systemic autoimmune diseases. [21] As a corollary, a variety of autoantibodies have been detected in patients with HIV infection. [22] , [23] , [24] , [25] , [26] , [27] .

Table 1 Classification as per the etiopathogenesis

Events in HIV infection

Rheumatological manifestations

Direct effects

Arthritis, myositis, vasculitis

Indirect effects

Chronic immune response to HIV antigens : humoral and cell mediated

B-cell hyperactivity, autoantibody production and non-specific symptoms of chronic immune stimulation

Lymphocytic infiltrative syndromes

e.g., DILS

Vasculitis

Inflammatory myopathy

Mediated by intact components (CD8 cells) of immune system

Reiter's syndrome, psoriatic arthritis

and other undifferentiated

spondyloarthropathies

Selective immune deficiency affecting

CD4 + "helper" T-cells

Opportunistic infection of musculoskeletal

system

Amelioration of CD4 dependent

rheumatic diseases e.g. RA

DILS: diffuse infiltrative lymphocytic syndrome

The various autoantibodies described in literature are given in Table 2

Table 2

Type

Subspecificity

Rheumatoid factor

Polyclonal, IgG, IgA, IgM

Antinuclear

dsDNA, Histone, Sm, U1RNP SSA

Antiphospholipid

IgG, IgM AntiB2GP-1

ANCA

PR3 and MPO

CLINICAL RHEUMATIC SYNDROMES

A number of rheumatic manifestations have been described in the course of HIV infections since the advent of this epidemic in the 80s. There are numerous case reports, case series, and reviews in this regard. Therefore a simplified scheme of rheumatic manifestations is warranted for ease of understanding as given in Table 3.

Table 3 Rheumatic disorders associated with or occurring in HIV-infected patients

Unique to HIV infection

Found in HIV infected patients

Ameliorated by HIV infection

Diffuse infiltrative leukocytosis syndrome (DILS)

Polymyositis

Rheumatoid arthritis

HIV associated arthritis

HIV associated Reiter's syndrome

Systemic lupus erythematosus (SLE)

Zidovudine associated myopathy

Psoriatic arthritis

Painful articular syndrome

Polyarteritis nodosa

Wegener granulomatosis

Henoch Schonlein purpura

Infectious arthritis

Diffuse Infiltrative Leukocytosis Syndrome (DILS) [28] , [29] 

The primary pathogenic association in these individuals is reflected as a distinct host immune response in individuals with the HLA-DR5 phenotype. [30] The association with HLA-DRB1 alleles expressing the ILEDE amino acid sequence in the third diversity region, usually HLA-DRB1*1102, DRB1*1301, and DRB1*1302 has delayed progression to AIDS in patients with DILS. This is due to delay in the evolution of the HIV-1 virus from the less aggressive M-tropic strain to the more rapidly replicating T-tropic strain. [31] Pathologically, there is evidence of focal sialadenitis, similar to that seen in Sjögren's syndrome, although there is less destruction of the salivary glands. CD8+ lymphocytes constitute the predominant inflammatory infiltrate, unlike that seen in non-HIV-associated Sjögren's syndrome. [32] 

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The defining presentation of DILS is a painless parotid enlargement that is often massive. The mean duration between the discovery of HIV seropositivity and onset of symptoms in one study was 3.4 years. [33] Submandibular and lacrimal gland enlargement often occurs together and is accompanied by sicca symptoms in more than 60% patients. In addition to glandular manifestations, there are a number of extraglandular features in these patients such as 7th cranial nerve palsy, aseptic lymphocytic meningitis, peripheral neuropathy, lymphocytic interstitial pneumonitis (LIP), lymphocytic hepatitis, renal tubular acidosis, interstitial nephritis, lymphoma, peripheral arthritis, and polymyositis. Significantly, the reported frequency of LIP was as high as 25-50% in patients with DILS. Since the introduction of protease inhibitors, this complication has become less frequent. The presence of renal tubular acidosis, lymphoma, and polymyositis in patients with DILS is associated with a poor prognosis.

The major features distinguishing this disorder from Sjögren's syndrome are shown in Table 4.

Table 4 Differences between diffuse infiltrative leukocytosis syndrome and Sjögren's syndrome

Feature

Diffuse infiltrative leukocytosis syndrome

Sjögren's syndrome

Sex distribution

Mainly men

Mainly women

Parotid swelling

Universal

Uncommon

Sicca symptoms

Common

Very common

Extraglandular symptoms

Common

Uncommon

Autoantibodies antinuclear antibodies, anti-Ro/La)

Rare

Common

Increased CD8+ T cells in blood

Present

Absent

For the diagnosis of DILS a diagnostic criteria [34] has been suggested, the patient must have

(1) HIV-seropositivity by ELISA and Western blot

(2) Bilateral salivary gland enlargement or xerostomia persisting for more than 6 months, and

(3) Histologic confirmation of salivary or lacrimal gland lymphocytic infiltration in the absence of granulomatous or neoplastic enlargement.

CT scanning has also been used to determine the extent of glandular swelling and evaluate parotid cysts and possible salivary glandular malignancy. Management depends on the extent of the manifestations. If the glandular swelling does not worry patients, and the sicca symptoms are mild or even absent, then reassurance and observation are enough. Pilocarpine in doses of 5-10 mg thrice daily may benefit sicca symptoms. In addition, regular dental care is needed.

There are some reports suggesting that moderate doses of corticosteroids (upto 30-40 mg prednisolone per day) might be useful in treating both the glandular swelling and sicca symptoms of DILS without adversely affecting the frequency of opportunistic infections, raising the viral loads or depressing the CD4 counts. [35] The effect is usually transient. Lymphocytic interstitial pneumonitis may require higher doses of corticosteroids (upto 60 mg/day of prednisolone), sometimes for extended periods. Antiretroviral therapy may be beneficial in glandular swelling and sicca symptoms.

HIV-associated Arthritis

This occurs in more than 10% patients in some reports. It was initially described as oligoarthritis, predominantly affecting lower extremities that tended to be self-limiting, lasting less than 6 weeks. Although early reports in western communities reported asymmetrical oligoarthritis as the usual pattern, polyarticular involvement is now seen frequently. [36] No mucocutaneous involvement is observed, and enthesopathy is also absent. There is no association with HLA-B27 or any other known genetic factor. Synovial fluid cultures are usually sterile. The synovial fluid leukocyte count is lower than that seen in HIV-associated reactive arthritis (500-2,000/µL). There may be a direct role of HIV as demonstrated by the isolation of HIV from a synovial fluid sample and electron microscopy showing particles resembling retrovirus. [37] X-rays of the affected joints are usually normal.

Treatment includes non-steroidal anti-inflammatory drugs (NSAIDs) and in more severe cases, low dose glucocorticoids. Patients may respond equally well to hydroxychloroquine and sulphasalazine. Most of the patients with HIV associated arthritis are in the late stage of infection. The etiology is still unclear, however recently both HTLV-I and -II have been suggested to induce inflammatory or autoimmune reactions which can increase significantly the incidence of arthritis.

Interferon-α used in the treatment of Kaposi sarcoma is known to cause arthralgia and myalgia. Rifabutin an anti-mycobacterial agent used may also cause arthralgia and myalgia. Indinavir, the protease inhibitor has also been implicated in causing monoarthritis though the exact cause was not explained.

Painful Articular Syndrome

The painful articular syndrome is characterized by bone and joint pain on movement, without evidence of synovitis. [38] It is a self-limiting syndrome which lasts less than 24 hours. This syndrome is usually observed in the late stages of HIV infection. The exact etiology is unclear, and treatment is symptomatic. [39] , [40] 

Myopathy

Muscle involvement in HIV infection covers a wide range of disorders ranging from uncomplicated myalgias and fibromyalgia to severe, disabling HIV associated polymyositis or pyomyositis. [41] , [42] , [43] . In one series of skeletal muscle biopsies performed in 92 adults with HIV infection at autopsy, there was atrophy in 51, inflammatory infiltrates in 8, necrosis in 8, and infection in 3. [44] HIV-associated polymyositis usually occurs early in HIV infection. The common presentation is of a subacute, progressive proximal muscle weakness with an elevated creatine kinase. [45] 

Electromyography shows myopathic motor unit potentials with early recruitment and full interference patterns, fibrillation potentials, positive sharp waves, and complex repetitive discharges. Histopathology reveals interstitial inflammatory infiltrates of variable intensity associated with degenerating and regenerating myofibrils, like those seen in polymyositis without HIV-1. Concomitant vasculitis is rare. Like HIV-negative patients, the predominant cell populations are CD8+ T cells and macrophages invading or surrounding healthy muscle fibers. It is controversial whether the virus directly leads to inflammatory myopathy. The treatment of HIV-associated polymyositis is similar to that for other inflammatory myopathies. Both the rise of creatine kinase and the muscle weakness respond to glucocorticoids. Refractory cases might need immunosuppressives such as methotrexate or azathioprine. These should, however, be used with caution.

Other muscle diseases in HIV-positive individuals include myalgia in 1/3rd of the patients and fibromyalgia in 10%. [46] , [47] Nemaline rod myopathy has been rarely described in HIV-infected individuals. [48] 

Diffuse myopathy has been reported with antiretroviral drugs, especially zidovudine. [49] Zidovudine causes reversible toxic mitochondrial myopathy manifested by myalgia, muscle tenderness, proximal muscle weakness, and elevated creatine kinase levels. The myopathy resolves on discontinuation of the medication. This condition is relatively rare in present era due to rarity of zidovudine use in developed nations. Even in developing nations the incidence has decreased as high dose zidovudine is precluded and increased awareness leading to early diagnosis of this condition. It is characterized by insidious onset of myalgias, muscle tenderness, and proximal muscle weakness after a mean duration of 11 months of therapy. It tends to be dose related, being associated with mitochondrial dysfunction. Both clinically, by EMG and by muscle biopsy, it is difficult to distinguish it from HIV-associated polymyositis, although the inflammatory infiltrates are less severe or sometimes absent in zidovudine induced myopathy. Consequently, in any HIV-infected individual who presents with an elevated CK and myalgia or muscle weakness, the drug should be discontinued for 4 weeks and the patient re-evaluated before EMG or muscle biopsies are undertaken. [50] 

Infective myositis (pyomyositis) can have a significant association with HIV infection. [51] Organisms implicated include staphylococcus aureus, salmonella enteritidis, microsporum, and toxoplasma.

HIV-associated Reiter's Syndrome and Reactive Arthritis

Reiter's syndrome, the first rheumatic syndrome reported in patients with HIV infection, can be severe, but whether it occurs more frequently in HIV-infected patients is controversial. [52] In two small retrospective studies where cohorts of HIV-infected patients were studied, the prevalence of Reiter's syndrome was between 5% and 10%, 100-200 times higher than the expected prevalence in the general population. [53] , [54] Another study of more than 1,000 homosexual men found the frequency of Reiter's syndrome to be only 0.3-0.5%, and there was no difference in the frequency between HIV-positive and HIV-negative subjects. [55] 

The commonest clinical presentation is that of a seronegative peripheral arthritis mainly involving the lower extremities, usually accompanied by enthesitis (sausaging of toes or fingers, Achilles tendinitis, and plantar fasciitis). Multidigit dactylitis, especially in the upper extremities, is common and may be relatively painless. Frank synovitis is less common but may occur at the ankle and the subtalar, metatarsophalangeal, and interphalangeal joints of the feet. Knee involvement is common, often asymmetric, and without radiologic changes. Hip involvement is uncommon. Synovitis of the wrist, elbow, and shoulder is uncommon but result in contractures and joint fusion. Enthesopathy may occur at the medial and lateral epicondyles, rotator cuff, or flexor tendons of the digits.

The axial skeleton is usually not involved, and although radiographs may show sacroiliitis, clinical sacroiliitis is uncommon. Mucocutaneous features especially keratoderma blennorrhagicum and circinate balanitis, are common. Psoriasiform skin rashes are also common and can be extensive; especially in patients not receiving anti-retroviral treatment. It can be difficult to distinguish HIV-associated Reiter's syndrome from psoriatic arthritis. Urethritis occurs as often as in HIV-negative Reiter's syndrome. Constitutional features of Reiter's syndrome, including weight loss, malaise, lymphadenopathy, and diarrhea, are difficult to distinguish from features of adrenal HIV disease. Amelioration is noted with onset of AIDS. Clinicians should recommend HIV testing for patients with Reiter's syndrome whose behavior puts them at an increased risk for HIV infection.

The treatment is similar to that of HIV-negative patients with Reiter's syndrome. NSAIDs are the mainstay of treatment. Indomethacin is often recommended, not only for its efficacy, but also for its unique inhibition of HIV replication observed in vitro. [56] Phenylbutazone is rarely used now because of its high side effect profile, but can be useful in refractory cases. Patients frequently have an inadequate response to NSAIDs alone. Second line agents like Sulfasalazine has been shown to be effective in some studies at doses of 1.5 to 2g/day [57] . Methotrexate was initially believed to be contraindicated because of its immunosuppressive effect and because it was reportedly associated with the development of Pneumocystis carinii pneumonia and other opportunistic infections. With careful monitoring of HIV viral loads and CD4 counts, and the patient's clinical status, more recent studies have shown a role for methotrexate in the treatment of Reiter's syndrome and psoriatic arthritis occurring in the setting of HIV infection. [58] Hydroxychloroquine has also been reported to be useful not only in treating HIV-associated Reiter's syndrome but also in reducing HIV replication as evidenced in various in vitro and in vivo studies. [59] Etretinate [60] can be useful for both arthritic and cutaneous manifestations. Research is also been done to evaluate the role of infliximab and other TNF blockers.

Psoriatic Arthropathy

Psoriatic arthritis, with or without psoriasis, occurs in HIV-infected persons with prevalence probably the same as that in non-HIV infected persons (1-2%). [61] This seronegative arthropathy is encountered with increased frequency in the HIV-positive population. Psoriatic arthropathy presents clinically with a number of patterns although there are no satisfactory diagnostic criteria. Signs and symptoms include pitting edema of the skin and subcutaneous soft tissues, enthesitis, synovitis, condylitis, dactylitis and peritendinitis. The foot and ankle are the commonest and most severe sites of inflammation.

Nail involvement is a common presenting symptom of psoriatic arthritis. Many patients with psoriatic skin manifestations or onycholysis only have these findings and do not meet the criteria for the diagnosis of psoriatic arthritis. The ray phenomenon, a combination of dactylitis and peritendinitis affecting the tendons of the same digit, may occur. Sacroiliitis and spondylitis have also been described. There is therefore considerable overlap with Reiter's syndrome and other connective tissue disorders and the descriptive term "undifferentiated spondylarthropathy" (described below) may be appropriate. [62] 

Unlike psoriatic arthropathy in the non-HIV infected population, which shows an association with HLA Cw6, B17, B7 Bw16 or Bw57, in HIV disease it is commonly associated with HLA B27. [63] , [64] The SAPHO syndrome is the co-occurrence of synovitis, acne, sterile skin pustules, hyperostosis, and osteitis. This rare manifestation of psoriatic disease is seen with increased incidence in HIV disease. [65] The imaging features depend on the spectrum of involvement. Non-specific swelling and lymphedema of tissues is not uncommon and produces a reticular pattern of increased density in subcutaneous fat on CT, or signal hyperintensity on T2-weighted MRI sequences and hypoechogenicity on ultrasound. In dactylitis the thickening affecting the soft tissues of a digit is associated with synovial thickening and peritendinitis.

Undifferentiated Spondyloarthopathy [66] 

Some HIV-infected patients fail to develop the entire spectrum of clinical manifestations for disease to be called as ankylosing spondylitis, Reiter's syndrome, or psoriatic arthritis, and are labeled as undifferentiated spondyloarthopathy. The epidemic of HIV infection in sub-Saharan Africa in recent years, however, has been associated with a dramatic upsurge in the prevalence of spondyloarthropathies other than ankylosing spondylitis, primarily reactive arthritis and undifferentiated forms of the disease, and less often psoriatic arthritis. HLA-B27, because of its rarity and virtual lack of association with the observed cases of spondyloarthropathy in this population, cannot be used as an aid in diagnosis of spondyloarthropathy in black Africans.

Conversely, HIV infection is increasingly showing such a strong association with reactive arthritis, psoriatic arthritis, and undifferentiated spondyloarthropathies in sub-Saharan African populations that any patient with acute or chronic inflammatory arthritis may need to be tested for possible HIV infection. [67] 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.

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. [68] Otherwise, treatment is symptomatic (NSAIDs); intralesional corticosteroids and sulphasalazine may be used in more extensive disease.

The treatment is similar to that for non-HIV infected patients. NSAIDs, such as indomethacin can be used initially for the joint symptoms, but results have been disappointing. There are reports that phenylbutazone (100 mg 3 times per day) is an effective drug and neutropenia is not a problem even in patients receiving zidovudine. Patients, in whom psoriatic joint disease does not respond to NSAIDs, may be treated with phenylbutazone or sulfasalazine (1-2 g/day). There is some data on second-line agents such as gold, methotrexate, and azathioprine. [69] Etretinate may also be helpful. The use of psoralen and pulsed UV-A phototherapy (PUVA) has helped the skin and joints of some HIV-infected individuals with psoriatic arthritis. Antiretroviral treatment has also been found to be helpful.

Septic Arthritis

In a prospective study among all new admitted patients with septic arthritis, 79% were HIV-1 seropositive. Gonococcal arthritis was found in 4 patients, all HIV positive. Non-gonococcal bacterial arthritis was established in 16 patients, of whom 13 were HIV positive. Causative organisms involved in this group were: Staphylococcus aureus, Streptococcus pneumoniae, Salmonella group B, Streptococcus group D, Klebsiella pneumoniae, and mycobacterium. Among atypical mycobacterium species, most commonly implicated are Mycobacterium avium intracellulare complex, M. kansasii, M. haemophilum, M. terrae, and M. fortuitum. Septic arthritis due to Haemophilus influenzae has also been described in a HIV-infected patient. [70] Fungal infections like Candida albicans also can manifest with oligoarthritis or polyarthritis. Thus, HIV-1 infection appears as a risk factor for septic arthritis patients, but it cannot be used as a predictor for HIV-1 infection for hospitalized patients. Septic arthritis occurs infrequently, and may present at any stage of HIV infection. [71] 

Osteonecrosis

Avascular necrosis or osteonecrosis usually involving the femoral head, has been reported in patients with HIV infection with or without other risk factors like steroid therapy or radiotherapy. The exact incidence is not known. It is postulated that either HIV-induced vasculopathy or HIV-associated antiphospholipid antibodies may be causal factor resulting in this condition. Typically patient presents with hip pain. But increasing use of MRI has revealed asymptomatic subclinical cases also. [72] , [73] 

Vasculitis

A whole spectrum of vasculitides has been described in patients with HIV infection. In one study, 23% patients with symptomatic disease had vasculitis. [74] 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 of 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. [75] , [76] , [77] . Corticosteroids remain the mainstay of treatment, although cytotoxic drugs also have been employed in refractory cases.

Vasculitis resulting from cytomegalovirus (CMV) infection can result in prominent gastrointestinal and cutaneous manifestations and its inclusion bodies can be demonstrated microscopically. In such cases, ganciclovir or foscarnet should be started and any concomitant immunosuppressive therapy reduced. [78] 

Natural Course of Other Rheumatological Diseases in HIV Infection

One of the biggest paradoxes of HIV infection is the finding of certain rheumatic diseases such as the DILS, reactive arthritis, Reiter's syndrome, or inflammatory myopathy occurring in the face of immunodeficiency. Alternatively, other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus have been reported as improving in the face of the CD4 lymphocytes depletion associated with this disease.

Initial studies indicated that rheumatoid arthritis underwent a remission with advancing HIV infection. [79] , [80] Subsequently, studies have indicated that active rheumatoid arthritis can coexist with HIV infection. [81] Systemic lupus erythematosus has been reported to coexist with HIV infection. [82] , [83] Initially, it was suggested that HIV infection could reduce lupus activity. Other studies have demonstrated that certain subsets of patients have a more rapid decline in the CD4 counts with rapid progression to clinical AIDS. [84] 

Lastly the following rheumatic conditions have also been associated with treatment with protease inhibitors: adhesive capsulitis, Dupuytren's contracture, and tenosynovitis of hand and feet. [85] 

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) is a collection of inflammatory disorders causing with paradoxical worsening of pre-existing infectious processes following the initiation of antiretroviral therapy in HIV patients. [86] , [87] , [88] , [89] . A number of autoimmune and musculoskeletal manifestations have been reported to occur during IRIS. These include self limiting musculoskeletal features like arthralgia and myalgias and sometimes transient synovitis. Sometimes flare of systemic rheumatic diseases like SLE, RA, polymyositis have also been reported to occur. [90] , [91] , [92] .

ROLE OF DMARDs AND IMMUNOSUPPRESSIVES IN THE MANAGEMENT OF INFLAMMATORY RHEUMATIC DISEASES ASSOCIATED WITH HIV INFECTION

As mentioned above disease modifying antirheumatic drugs and other biological response modifiers are not contraindicated in treatment of systemic rheumatic diseases associated with HIV infection. But the same are to be used with caution in view of risk of immunosuppression, resultant opportunistic infections and risk of progression of HIV infection. [93] A number of reports of successful use of sulfasalazine, methotrexate, and cyclosporine in HIV associated rheumatic diseases have led to increasing and earlier use of disease agents. [94] , [95] , [96] , [97] . In addition infliximab and etanercept which are anti-TNF biologic response modifiers have been found to be safe in HIV associated rheumatoid arthritis and spondyloarthropathies. However, in developing countries like India extreme caution is to be exercised due to high prevalence of tuberculosis in the community and due to the fact that incidence of tuberculosis is increased manifold both due to HIV infection and anti-TNFα use (double jeopardy). [98] , [99] , [100] .

CONCLUSION

HIV infection is associated with a number of musculoskeletal diseases both inflammatory and non-inflammatory. Extensive and earlier use of antiretroviral therapy has altered the profile of rheumatic manifestations. While there has been significant decrease in inflammatory spondyloarthropathies and other inflammatory arthritis, certain rheumatic diseases like osteonecrosis, osteopenia and immune reconstitution inflammatory syndrome are increasingly being recognized. Due to better survival and increasing prevalence of HIV infections, the profile of rheumatic diseases will continue to evolve and rheumatologists need to be aware of this in future.