Rheumatological disease

Adam Jenney : Visiting Professor of Medicine, College of Medicine, Nursing and Health Sciences, Fiji National University, Suva, Fiji Islands Honorary Consultant, The Alfred Hospital, Melbourne, Victoria, Australia

Symptomatic disease of joints and muscles is common, particularly in ageing populations and people with human immunodeficiency virus (HIV) infection are no exception. Moreover there are some rheumatological diseases that are more common in the setting of HIV regardless of age. Some conditions may occur at any stage of the illness (perhaps the first manifestation of HIV) whereas others may be seen with advancing immunosuppression as the disease progresses. The major rheumatological conditions associated with HIV are listed in Table 1.

Table 1. The major rheumatological conditions associated with HIV - adapted from Espinoza[1]
Arthralgia and myalgia 
Arthritis

HIV- related arthritis

Painful articular syndrome

Spondyloarthropathies

(Ankylosing spondylitis)

Reactive arthritis

Psoriatic arthritis

Gout 
Rheumatoid arthritis 
ART-associated arthritis 
Avascular necrosis 
Diffuse infiltrative lymphocytosis syndrome 
Vasculitis 
Systemic lupus erythematosus
Bacterial infections

Septic arthritis

Pyomyositis

Myopathy 
Polymyositis 
Dermatomyositis 
Zidovudine myopathy 
Inclusion body myositis 
Nemaline bars 

Arthralgia and myalgia

Arthralgia and myalgia are common during the HIV seroconversion illness and remain a source of frequent symptoms thereafter. The arthritis is usually polyarticular but intermittent and often quite mild. Myalgia is probably even more common and in some studies is cited as a bothersome chronic symptom in up to half of the patients.[2] In an outpatient population with HIV of 300, in a 12-month period, 46.7% had body ache and 26.7% complained of arthralgia.[3] Rest and simple treatment such as non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol are usually sufficient.

Arthritis

HIV-related arthritis

HIV-associated arthritis usually affects the knees and ankles symmetrically and may last for a few days or several months.[4] For treatment, NSAIDs are often all that are necessary but persistent debilitating disease might need a corticosteroid injection.

Painful articular syndrome

This condition manifests as acute severe, sharp arthritic pain that may last for a few hours to a few days. It particularly affects the knees, elbows or shoulders especially in those with more advanced immunosuppression and was first described in 1980s.[5] Treatment includes NSAIDs but narcotics are sometimes needed.

Spondyloarthropathies

These diseases are a family of inflammatory arthropathies most commonly seen in men that involve the spine (spondylitis) but may start at the sacro-iliac joints. Characteristically the distal arthritis is asymmetrical and mainly in the lower limbs. The HLA B27 antigen is frequently present but rheumatoid factor is negative. (The archetypical spondyloarthropathy is ankylosing spondylitis, however it is not commonly seen in patients with HIV infection)

Reactive arthritis

The association of reactive arthritis with HIV infection is controversial. Initially it was found to be more common in patients with HIV with a prevalence of between 1.7 and 11.2%.[6] However, another large study found it no more common than in the general population.[7] More recently in the era of effective antiretroviral therapy (ART), diagnoses seem much rarer: the prevalence rate was 2.3% in Kole’s 2013 study in India and a US survey of 888 patients with HIV between 1995 and 2006 found that 9% had a rheumatological diagnoses but there was not a single case of reactive arthritis.[8]

This condition usually manifests as oligoarthritis of the lower limbs that follows an infection of the genitourinary or gastrointestinal tracts after 1 to 6 weeks. It also has been seen as part of immune reconstitution syndrome.[9] The arthritis can be severe and progressive affecting sacro-iliac joints and may cause tense effusions of the knee, ankle and foot joints. While mainly in the lower limbs it may also affect the wrist and hands. Enthesopathy (the inflammation of the periarticular connective tissues such as ligaments, tendons, joint capsules and fascial bands) may be a prominent feature. The symptoms may last for several weeks to months though the arthritis may be mild and intermittent over that time. (Reiter syndrome, which describes the triad of symptoms, reactive arthritis, conjunctivitis and urethritis, is a subset of reactive arthritis and is an eponymous term that is fading from use).

When only one joint is involved, a joint aspiration is often prudent to exclude septic arthritis. In reactive arthritis the joint may well have neutrophils (though the fluid should not look purulent, and will be culture negative as it is an immunological reaction to the triggering infection rather than dissemination of the actual microorganism.

Non-articular manifestations of reactive arthritis, including circinate balanitis and keratoderma blennorrhagicum, may be more common in patients with HIV. Probable infectious triggers include Chlamydia trachomatis, Campylobacter, Salmonella, Shigella and Yersinia species.[10] Screening and prescribing treatment for the triggering infection may be prudent, especially if it is thought to be Chlamydia trachomatis, although many of the gastrointestinal causes will not be detectable at the time of the arthritis.

Treatment for the arthritis includes NSAIDs and simple analgesia for mild disease, but disease-modifying agents like sulfasalazine, hydroxychloroquine and even methotrexate have been used in more severe chronic cases. Oral and intra-articular corticosteroids might also be needed.[11] Triamcinolone injections should be avoided in patients receiving ritonavir as iatrogenic Cushing syndrome has been induced.[12]

Psoriatic arthritis

Psoriasis has a similar prevalence in the population with HIV as it does in the general population although it tends to be more severe and is more likely to present in different forms concurrently e.g. guttate and erythrodermic psoriasis occurring together.[13] Psoriasis is a T cell-mediated disease and worsens with the progression of HIV, especially when the CD4 T-lymphocyte (CD4) cell count falls below 100 cells/μL. Psoriatic arthritis is classified as a severe manifestation of psoriasis and it can be destructive and debilitating. In contrast to rheumatoid arthritis (see below), where CD4 IL-17 cells significantly contribute to the inflammation, in psoriatic arthritis the IL-17 response involves CD8+ and innate lymphocytes.[14] The development of arthritis due to psoriasis should prompt dermatologists and rheumatologists to consider testing for HIV.[15] It may cause symmetrical arthritis with the classical dactylitis (sausage digits) or enthesitis or nail changes (these may sometimes be confused with onychomycosis, which is also more common in HIV). A more classical psoriatic spondylitis may occur with morning stiffness, vertebral column pain and sacroileitis. The pathogenesis of this diverse array of diseases has been more recently linked to the IL23/Th17 axis, where an aberrant interaction of innate and adaptive immunity leads to tissue inflammation and destruction.[16][17]

Treatment of psoriasis in HIV patients includes ART but refractory disease may need hydroxychloroquine and methotrexate; even cyclosporine and tumour necrosis factor inhibitors might be needed.[18]

Gout

Gout is thought to be more common in people with HIV though little data support this assumption.[19] Treatment remains the same relying both on prophylaxis and acute measures for flares. It should be noted that didanosine is contraindicated with allopurinol (didanosine levels can become toxic) and, while colchicine remains very useful, levels of colchicine may become elevated with concurrent protease inhibitor use.[20]

Rheumatoid arthritis

The inflammation of rheumatoid arthritis is dependent on CD4 cells and therefore, not surprisingly, has been rarely documented in the setting of HIV. However rheumatoid arthritis does occur in some patients causing the typical erosive, distal, small-joint polyarthropathy with the presence of rheumatoid factor and anti-CCP.[21] (Note: in the absence of arthritis low-titre, false positive rheumatoid factor and anti-CCP results have been recorded in patients with advanced HIV.[22])

Rheumatoid arthritis has emerged after the commencement of ART as an immune reconstitution disorder but not frequently.[23] Treatment is standard with NSAIDs and the early introduction of disease-modifying agents, as required.

ART-associated arthritis

Among the older protease inhibitors, indinavir has been known to cause arthralgia, arthritis and capsulitis, tenosynovitis and Dupuytren contracture.[24] The arthritis has been sometimes due to deposition of indinavir crystals in the joint. (Arthralgia, rather than arthritis, has been reported with the use of lopinavir/ritonavir, lamivudine, tenofovir, nevirapine and more recently maraviroc.[25])

Avascular necrosis

Avascular necrosis (AVN) of bone is more common in patients with HIV than in the general population. AVN mainly manifests in the femoral head but it can occur in the tibial plateau, humeral head, talus and elsewhere. It may be linked to HIV itself (particularly in those with low CD4 nadirs), the duration of ART, smoking, hyperlipidaemia, vasculitis, anti-phospholipid syndrome and corticosteroid use.[26] Early in their use, protease inhibitors were thought to cause AVN but this was not supported by case-control studies,[27] although a recent meta-analysis just grazed significance with an odds ratio of 2.09 (p = 0. 05) to again perhaps link protease inhibitor use with AVN.[28]

Diffuse infiltrative lymphocytosis syndrome

Diffuse infiltrative lymphocytosis syndrome (DILS) affects 3 - 7.8% of people with HIV infection. It causes parotid enlargement, xerostomia and xerophthalmia, and is mediated by CD8+ T cells. Extra-glandular involvement is common, with lymphocytic interstitial pneumonitis occurring in 31%, myositis in 26% and hepatomegaly in 23% of cases. Less commonly the gastrointestinal tract, kidneys and peripheral nerves (often cranial nerve VII) may be affected.[29] Unlike Sjogren syndrome (which is CD4 cell driven), auto-antibodies, such as rheumatoid factor, antinuclear, Ro and La antibodies, are not present.[30] High-dose oral glucocorticoids for 2 to 3 months with ART may be required. ART, sometimes with a low-to-moderate dose of oral corticosteroids, can reduce parotid swelling and the sicca symptoms and even improve the neuropathy.[31][32] (The Sicca syndrome - dry eyes and mouth, and parotid enlargement - occurs in 25% of affected patients. Symptomatic relief can be gained with artificial tears and saliva.)

Vasculitis

There is a wide variety of documented cases of vasculitis occurring in patients with HIV. These include diseases that affect large (e.g. Giant cell arteritis), medium-sized (e.g. Kawasaki-like disease) and small (e.g. Henoch-Schonlein pupura) arteries. Polyarteritis nodosa may occur in a so-called non-classical form with predominantly musculoskeletal symptoms. It can also cause neurological manifestations such as mononeurits multiplex.[33] Treatment is usually successful with corticosteroids, though intravenous immunoglobulin and cyclophosphamide have been used for more severe symptoms.[34]

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune condition that affects the joints, skin, kidneys, nervous system (among other organs), predominantly of women, and is associated with the production of anti-nuclear antibodies. While it is rarely seen with HIV it does occur and some patients have experienced improvement of their SLE symptoms after the diagnosis of HIV infection. The corollary has also been seen with reactivation of SLE symptoms after starting ART.[35] Management can be complex and a variety of immunosuppressive agents might need to be tried.

Bacterial Infections

Septic arthritis

Septic arthritis is not frequently seen in patients with HIV infection, though it may be more common in people who inject drugs.[36] An acutely inflamed single joint requires urgent investigation to rule out bacterial infection. The commonest aetiology is Staphylococcus aureus but streptococci (and potentially Pseudomonas in people who inject drugs) are also seen. Aggressive joint lavage and systemic antibiotics can arrest a potentially rapidly progressive and destructive infection. Cultures of blood and synovial fluid are essential for diagnosis and selection of an appropriate antimicrobial agent.

Tuberculous arthritis occurs quite commonly in developing countries and acute Neisseria gonhorrea arthritis can be seen in patients with disseminated gonococcal infection. Particular consideration should be given to opportunistic pathogens (e.g. non-tuberculous Mycobacteria and fungi such as Candida, Cryptococcus and Sporothrix), especially when CD4 cell counts have fallen to < 100 cells/μL.[37][38]

Pyomyositis

Pyomyositis may occur as single or multiple abscesses, spontaneously or after trauma (e.g. an intramuscular injection). Gram positive (e.g. Staphylococcus aureus, Streptococcus pyogenes) and Gram negative organisms (e.g. Escherichia coli) may cause this infection, although opportunistic infections such as toxoplasmosis, mycobacteria and Cryptococcus should also be considered in more advanced HIV disease. Pyomyositis may follow an indolent course at first but treatment usually requires surgical drainage and targeted systemic antibiotics.[39][40]

Myopathy

Polymyositis

Polymyositis may occur at any stage of HIV infection, though often quite early in the course. The patient typically presents with myalgia, proximal muscle weakness and wasting, and the symptoms vary from mild to severe. The serum creatine kinase (CK) level may be markedly elevated, in keeping with a destructive inflammatory myositis that can be diagnosed on biopsy where there may be a significant CD8+ lymphocyte infiltrate.[41] However, sometimes the inflammatory response may be quite mild.[42] High-dose oral corticosteroids (e.g. prednisolone 0.5-1 mg/kg daily) are often required, with improvement occurring over 1 to 2 months. Sometimes azathioprine or methotrexate is needed for recalcitrant disease.[43]

Zidovudine myopathy

A major differential diagnosis of myalgia or muscle weakness is zidovudine myopathy, which can occur 3 to 21 months after commencing the drug. It was more common when larger doses of zidovudine, a nucleoside analogue reverse transcriptase inhibitor (NRTI), were used and the pathogenesis is probably related to mitochondrial toxicity, although this may not be the sole mechanism. The patient presents with proximal muscle weakness, sometimes of insidious onset with the legs more commonly affected than the arms, and a two- to six-fold rise in creatine kinase (CK).[44] Histology and electron microscopy show only limited lymphocyte infiltration, ragged red fibres, accumulation of glycogen and lipids, and abnormal mitochondria. Zidovudine should be ceased and improvement follows in 1 to 2 months though this may be helped by the use of corticosteroids. Other NRTIs have very rarely been known to cause a similar myopathy.

Dermatomyositis

This is a rare condition characterised by proximal muscle weakness and wasting with a characteristic rash on the upper torso and face. There are autoantibodies present. Treatment usually requires high dose corticosteroids, sometimes as pulses of methyl prednisolone.[45]

Other myopathies

Inclusion body myositis can affect both proximal and distal muscle groups and initially has a very elevated CK that soon settles to be chronically, though moderately, supra normal. The histology is characteristic with muscle fibres showing vacuolation plus the deposition of amyloid-like material. There is a CD8+ lymphocyte infiltrate present. Corticosteroids and immunosuppressive agents are disappointing in providing treatment but intravenous immunoglobulin may be of benefit.[46]

Nemaline rod myopathy is a rare condition that is usually congenital but has been found in the setting of HIV. There is proximal wasting and weakness, and the muscle biopsy has large numbers of abnormal actin thread-like inclusions. Corticosteroids, intravenous immunoglobulin or plasmapheresis may produce some improvement.[47] A wasting myopathy may occur during advanced HIV infection. This condition may cause a mild rise in CK, but is not associated with inflammatory cells. A necrotising myopathy has also been documented; the aetiology is unknown but this, similarly, is not an inflammatory myopathy.[48]

Severe life-threatening rhabdomyolysis resulting in renal failure has been reported due to HIV drug interactions e.g. protease inhibitors inhibiting the action of the CYP3A4 enzyme potentially resulting in extremely high levels HMG CoA reductase inhibitors (statins) e.g. simvastatin and lovastatin. These combinations are contraindicated.[49] Rhabdomyolysis has also complicated primary HIV infection but also can occur later in the course of the infection.

Other myopathies reported in people with HIV infection include myasthenia gravis and a myopathy associated with malignancies such as non-Hodgkin lymphoma.

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