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ARTICLAR SYNDROMES ASSOCIATED WITH HIV INFECTION – AN UPDATE Professor Girish Mody


HIV prevalence epidemic curve among antenatal women, 1990-2008


RHEUMATIC SYNDROMES WITH HIV INFECTION MUSCLE DISEASES - rhabdomyolysis, zidovudine myopathy, polymyositis, dermatomyositis, pyomyositis, nemaline rod myopathy BONE – osteoporosis, osteomalacia, osteomyelitis VASCULITIS – PAN, HSP. Large vessel vasculitis DILS IRIS e.g. RA, SLE SEROLOGIC ABNORMALITIES – ANF, ANCA, APL, Anti-CCP, RF


SPECTRUM OF HIV ASSOCIATED ARTICULAR DISORDERS ARTHRALGIA PAINFUL ARTICULAR SYNDROME HIV ASSOCIATED ARTHROPATHY SPONDYLOARTHROPATHY (SpA) -Reactive arthritis -Psoriatic arthritis -Undifferentiated SpA

OSTEONECROSIS SEPTIC ARTHRITIS DRUG RELATED SIDE EFFECTS GOUT


ARTICULAR SYNDROMES WITH HIV ARTHRALGIA Most common rheumatic manifestation 12 - 40% Occurs at any stage of the disease Most commonly oligoarticular Mild to moderate intensity


ARTICULAR SYNDROMES WITH HIV PAINFUL ARTICULAR SYNDROME Severe intermittent pain Less than 4 joints No evidence of synovitis Short duration (< 24 hours) Usually later stage of the disease


HIV ASSOCIATED ARTHRITIS A) Oligoarticular, asymmetrical peripheral arthritis Commonly knees and ankles Severe pain and disability Acute onset, especially males Self limiting course

B) Polyarticular erosive similar to RA


HIV ASSOCIATED ARTHRITIS IN CONGO BRAZZAVILLE Ntsiba H et al Med Mal Infect 2007;37: 758 - 761

306/ 3042 (10%) patients in rheumatology clinic were HIV positive 220 (7.2%) had a rheumatologic manifestation 158 (71.8%) had HIV related arthritis Polyarthritis 83.5% Oligoarthritis 16.5% Symmetrical 97.5% Great toe 23% Resolved within 2-5 weeks with NSAIDs


REACTIVE ARTHRITIS AND REITER’S SYNDROME Commoner with homosexual than IVDU Also reported in heterosexual population in Africa Associated with dysentery or urogenital infection May be presenting manifestation of HIV infection Incomplete form of Reiter’s common


REACTIVE ARTHRITIS AND REITERâ&#x20AC;&#x2122;S SYNDROME Extra-articular features include enthesitis, onycholysis, balanitis, keratoderma, mouth ulcers and uveitis HLA B27 positive in 80-90% of Caucasians Majority of Africans are HLA B27 negative Rx - NSAIDS - Sulphasalazine, HCQ, ? MTX * Indomethacin and HCQ inhibit viral replication


ARTICULAR MANIFESTATIONS OF HIV Initial reports of Reactive arthritis (Reiterâ&#x20AC;&#x2122;s syndrome) Studies in Argentina and Mexico showed a significant increase in rheumatic manifestations in patients compared to controls with similar risk factors Increased prevalence of SpA in Africa


PSORIATIC ARTHRITIS Increased prevalence of psoriasis 1 - 20% Increased prevalence of psoriatic arthritis 1 - 32% Polyarticular asymmetric pattern of arthritis Enthesopathy and dactylitis occur Axial skeleton less commonly involved Course of disease is variable


PSORIATIC ARTHRITIS AND HIV INFECTION IN ZAMBIA Njobvu P, McGill P. J Rheumatol 2000; 27: 1699 - 1702

28 patients with psoriatic arthritis of whom 27 were HIV positive The arthritis was predominantly polyarticular, lower limb and progressive Amelioration of symptoms with the onset of AIDS


UNDIFFERENTIATED SPONDYLOARTHROPATHY Usually presents with enthesitis • plantar fasciitis • achilles tendonitis


AVASCULAR NECROSIS OF BONE • Corticosteroids • HIV related • HAART (protease inhibitors) • Protein S deficiency • Anti-phospholipid antibodies • Hyperlipidaemia • Vasculitis


OSTEONECROSIS Monier P et al (2000) – review of 33 cases - Mean age 35 years - 55% (18) on ARV (all on nucleosides,15 on AZT, 7 on PI’s, 2 on Non-nucleoside analog). - 33% HIV sole risk factor - 21% Steroids - 21% IV drug abuse - 12% Alcohol abuse - 19% APL antibodies - 12% Hyperlipidaemia


OSTEONECROSIS USA (2001) 17 patients vs. 34 controls – corticosteroids, increase in CD4 from nadir, P. Carinii pneumonia. France ( 2005) 12 patients vs. 36 controls – current alcohol consumption, history of corticosteroid use. Switzerland (2004) 26 patients vs. 260 controls – higher BMI and severe immunosuppression, not related to ARV.


SYMPTOMATIC OSTEONECROSIS Taiwan (2007) 11/967 patients – 1.1% – Prolonged exposure to NRTI and HAART, higher triglycerides and higher proportion of lipodystrophy

France (2006) 104/56393 patients 0.18% – Prior AIDs defining illnesses, CD4 cell nadir and exposure to HAART ( RR from 2.6 with <12 months to 5.1 for >60 months )


OSTEONECROSIS Miller et al (2002) USA - 15/339(4.4%) of asymptomatic HIV infected adults on MRI Morse CG et al (2007) â&#x20AC;&#x201C; 3/239 second MRI median 23 months (incidence 0.65/100 person years) HIV infected patients have 100 fold increased risk of ON vs. general population


SEPTIC ARTHRITIS Septic arthritis, bursitis and osteomyelitis Usually monoarticular Staphylococcus, gonococcus, salmonella Candida and TB more common Opportunistic infections also occur


SEPTIC ARTHRITIS Staphylococcus aureus Staphylococcus epidermidis Neisseria gonorrhoeae Salmonella Atypical mycobacteria

Mycobacterium tuberculosis Candida albicans Streptococcus pyogenes group A Meningiococcus Treponema pallidum


SEPTIC ARTHRITIS

Zalavras CG et al Clin Orthop Rel Res 2006;451: 46 - 49

19 patients with septic arthritis (USA) Mean CD4 was 154 ( range 7 - 482) -11 <200 Most common was Staph. aureus (ORSA) in 6 patients Mycobacterial infections in 3 patients Monoarticular in 14 and polyarticular in 5 All patients with mycobacterial infections and 4 of the 5 patients with polyarticular infections had CD4 <200 cell


RELATED TO ARV DRUGS Mono or oligoarthritis Arthralgia Adhesive capsulitis


HYPERURICAEMIA AND GOUT High frequencies of hyperuricaemia have been reported Few cases of gout also reported Raised uric acid related to increased cell turnover from viral replication and ARV such as stavudine and didanosine Mitochondrial toxicity with ARV leads to - lactate formation which stimulates urate reabsorption in the proximal tubules - ATP depletion which leads to urate production in the purine nucleotide cycle


DIFFUSE INFILTRATIVE LYMPHOCYTOSIS SYNDROME Enlargement of the parotid, submandibular and lacrimal glands â&#x20AC;&#x201C;sicca symptoms 3-4% prevalence Extra glandular manifestations â&#x20AC;&#x201C; lymphocytic interstitial pneumonitis, peripheral neuropathy, polymyositis, cranial neuropathy, lymphocytic hepatitis, renal tubular acidosis Auto antibodies negative Diagnosed by salivary gland biopsy or gallium scanning Responds to HAART +/- steroids


Rheumatic manifestations of HIV in the era of HAART


EFFECTS OF HAART Reactive arthritis and psoriatic arthritis as well as the painful articular syndrome are less common DILS is also less common Reduced opportunistic infections Improved survival


EFFECTS OF HAART NEW OBSERVATIONS Metabolic syndrome with redistribution of body fat, insulin resistance, hyperlipidaemia Hyperuricaemia Osteonecrosis Osteopaenia and accelerated bone loss IRIS Reports of TMJ dysfunction, frozen shoulder, Dupuytrenâ&#x20AC;&#x2122;s contracture etc with protease inhibitor therapy Only 4 of 128 patients on HAART developed rheumatic disease after a mean of 2.6 years treatment


IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

Exacerbation of auto immune and auto inflammatory syndromes with successful treatment of HIV Autoimmune thyroiditis Sarcoidosis RA, SLE, polymyositis â&#x20AC;&#x201C; 80% occur de novo Mean onset about 9 months


IRIS CRITERIA Pre- existing AIDS Response to HAART with increased CD4 and reduced viral load Increased risk when CD4 below 200 cells High antigenic burden with opportunistic infections Stop HAART if CNS or eyes involved Most resolve spontaneously and can continue Rx


HIV in RA and SLE patients With HIV infection, decreased CD4 cells, production of interferon gamma decreases â&#x20AC;&#x201C; increase in anti-inflammatory cytokines IL-4 and IL-10 and decreased Th1 response RA and SLE can become quiescent With HAART, immune reconstitution occurs and SLE and RA can worsen or or new onset RA and SLE can occur as the immune system recovers


RHEUMATIC MANIFESTATIONS IN HIV POSITIVE PATIENTS (n=458) Reveille J.D. Semin Arthritis Rheum 2000; 30; 3 : 147-166

Bursitis/Tenosynovitis Osteoarthritis HIV associated arthralgia Reactive/Psoriatic arthritis HIV associated arthritis Gout Infectious arthritis SLE AS

19% 7% 6% 4% 4% 2% 1% 1% 0.5%


RHEUMATIC MANIFESTATIONS IN HIV POSITIVE PATIENTS (Reveille J.D. N = 458) DILS Low back pain Elevated CK Parotid enlargement Fibromyalgia Hepatitis B/C syndromes HIV associated polymyositis Sicca symptoms Vasculitis

21% 7% 6% 5% 4% 3% 2% 1% 1%


RHEUMATIC MANIFESTATIONS OF HIV Yao Q et al Clin Exp Rheumatol 2008;26:799-806

Present in 80 /888 (9%) of HIV patients Arthritis/ arthralgia 49 5.5% Septic arthritis 9 1.0% Osteomyelitis 8 0.9% Avascular necrosis 6 0.7% CTDx (SLE 3 RA 2 PM 1 6 0.7% No cases of spondyloarthropathies


AUTOANTIBODIES IN HIV INFECTION (n = 84) Anticardiolipin antibodies ANCA C-ANCA ANF Smooth muscle antibodies

81% 31% 30% 12% 39%


ANTI-CCP ANTIBODIES IN HIV AND TB TB – Anti-CCP antibodies positive in 32% of 47 patients and in 37% of 49 patients with TB Elkayam O et al Ann Rheum Dis 200;65:1110-1112. Kakumanu P et al Arthritis Rheum 2008; 58: 1576 – 1581.

HIV – Anti-CCP antibodies were positive in 15% of 60 patients with HIV prior to HAART and 4% after 6 months treatment du Toit R et al J Rheumatol 2011;38: 1-6.


HIV Arthritis in Children Durban, South Africa Chinniah et al 2006 153 Children seen 132 tested for HIV 35 (27%) HIV positive 97 (73%) HIV negative


ARTHRITIS IN ASSOCIATION WITH HIV INFECTION IN BLACK AFRICAN CHILDREN : CAUSAL OR COINCIDENTAL? HIV +ve n= 35(%)

HIV –ve n= 97(%)

p Value

Systemic Onset

0 (0)

16 (16)

0.01

Oligoarthritis

9 (26)

38 (39)

0.15

Polyarthritis

14 (40)

38 (39)

0.93

Spondyloarthropathy

12 (34)

5 (5)

<0.001


EVIDENCE TO SUPPORT A CAUSAL ROLE FOR HIV INFECTION IN CHILDREN WITH ARTHRITIS 1) HIV infection in 27% of 132 children with

arthritis. (Expected prevalence of 5.6% in 2 â&#x20AC;&#x201C; 14 year age group)

2) The higher proportion of males in HIV positive children compared to HIV negative JIA M:F 2.5 : 1 (n = 35) HIV positive 0.9 : 1 (n = 97) HIV negative 0.5 : 1 (n = 521) JIA in UK


EVIDENCE TO SUPPORT A CAUSAL ROLE FOR HIV INFECTION IN CHILDREN WITH ARTHRITIS 3) Systemic onset JIA 16% (n = 97) 0% (n = 35) 14% (n = 521)

HIV negative JIA HIV positive children JIA in UK

4) Significantly higher prevalence of spondyloarthropathy in 34% of HIV + compared to 5% of HIV â&#x20AC;&#x201C; children (p<0.001)


SPECTRUM OF ARTICULAR MANIFESTATIONS WITH HIV INFECTION IN AFRICA HIV SEPTIC ASSOCIATED ARTHRITIS ARTHRITIS

COUNTRY NUMBER

SPA

OTHER

Zambia

289

222

-

66

1

Zimbabwe

64

27

-

34

1

Rwanda

26

10

9

4

3

Congo

39

2

2

32

3

South Africa

78

15

7

49

7


ARTICULAR SYNDROMES WITH HIV INFECTION ARTHRALGIA PAINFUL ARTICULAR SYNDROME SEPTIC ARTHRITIS SPONDYLOARTHROPATHY Reactive arthritis / Reiter’s syndrome Psoriatic arthritis Undifferentiated spondyloarthropathy HIV ASSOCIATED ARTHRITIS OSTEONECROSIS

GOUT Associated with ARV – adhesive capsulitis , arthritis



C24 - MODY - HIV infection2