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Joint Bone Spine 80 (2013) 426–428

Available online at

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ase report

uccessful use of antitumor necrosis factor-alpha biological therapy in managinguman immunodeficiency virus-associated arthritis: Three case studies fromaudi Arabia

ani Almoallima,∗,b,c, Ibtisam Jali b, Ghassan Walia,b

Department of Medicine, Medical College, Umm Alqura University, PO Box 1821, 21441 Jeddah, Saudi ArabiaDepartment of Medicine, King Faisal Specialist Hospital, Jeddah, Saudi ArabiaAlzaidi Chair of Research in Rheumatic Diseases, Umm Alqura University, Makkah, Saudi Arabia

a r t i c l e i n f o

rticle history:ccepted 7 January 2013vailable online 1 March 2013

eywords:IV-associated arthritisIV infectioniologic therapyolyarthritisethotrexate

nti-TNF-alpha

a b s t r a c t

Arthralgic disorders involving various rheumatic manifestations are commonly observed in HIV patients.Available therapies for HIV-associated rheumatic syndromes include non-steroidal anti-inflammatorydrugs for pain management, disease-modifying antirheumatic drugs (e.g., methotrexate), and antitu-mor necrosis factor-alpha therapies. However, treatment of HIV-associated arthritis can be challenging,particularly in patients with co-infections like hepatitis viruses, and therapeutic strategies are not welldefined. Here, we present three case reports on the use of antitumor necrosis factor-alpha agents forHIV-associated arthritis. We managed three cases of HIV-associated arthritis following initial presenta-tion. All patients were on highly active antiretroviral therapy with stable HIV loads and CD4+ cell counts.Data were reported for treatment of inflammatory arthritis using 5 months of etanercept followed byadalimumab for case 1, and 12 months of etanercept for case 2. In case 3, reactive arthritis was treatedwith 5 months of etanercept followed by adalimumab. In all three cases, significant improvement or

resolution of arthritis was achieved following treatment with antitumor necrosis factor-alpha therapies.Moreover, these case studies demonstrated the safe and effective use of antitumor necrosis factor-alphaagents in HIV patients with hepatitis B and/or C virus co-infection. Our results indicate that antitumornecrosis factor-alpha therapies can be successfully used for HIV-infected patients with stable HIV loadsand CD4+ lymphocyte counts.

nc ais

© 2013 Société fra

. Introduction

HIV patients can be affected by various rheumatic syn-romes, including arthralgic disorders [1]. The pathophysiologyf HIV-associated arthritis is poorly understood, but its under-ying mechanisms appear to be complex and multifactorial [2].IV-associated rheumatic symptoms can be induced directly byIV infection, or through indirect mechanisms involving micro-ial infection or adaptive immune responses. Classification ofIV-associated arthritis is difficult, in part because rheumatic

mmunological markers are typically negative in HIV patients.owever, while clinical presentation of arthritis can vary, HIV-ositive and negative individuals display arthritis similarly [2].

Here, we present three case reports regarding the use of anti-umor necrosis factor-alpha (TNF�) therapies in patients withIV-associated arthritis, with two cases involving HBV and/or HCV

∗ Corresponding author. Tel.: +966 5 05 70 39 35; fax: +966 2 527 0000x7110.E-mail address: hanialmoallim@hotmail.com (H. Almoallim).

297-319X/$ – see front matter © 2013 Société franc aise de rhumatologie. Published by Eoi:10.1016/j.jbspin.2013.01.002

e de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

co-infection. The following outcomes suggest that biologic thera-pies, like etanercept and adalimumab, can be safely and effectivelyused on patients with stable HIV loads and CD4+ cell counts.

2. Results

2.1. Case 1

A 33-year-old female with known HIV infection since Febru-ary 2009 was followed up by the HIV clinic’s Infectious Diseasesservice and started on highly active antiretroviral therapy (HAART):Atripla® (efavirenz/emtricitabine/tenofovir). In November 2011,she was referred to the Rheumatology service for joint pains. Shereported pain and swelling in both wrists as well as the small jointsof the hands, with morning stiffness for 15 minutes and a mildimpact on her daily activities. Symptoms had persisted for 2 months

and were not improved by non-steroidal anti-inflammatory drugs(NSAIDs). She did not report any previous episodes of joint dis-comfort. Apart from being HIV-positive, the patient had no historyof viral infection and displayed no indication of connective tissue

lsevier Masson SAS. All rights reserved.

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isease or psoriasis, but there was a positive family history of pso-iasis (father).

Physical examination indicated wrist swelling and tendernessf both hands, involving the third and fourth metocarpophalangealMCP) joints and the second and third proximal interphalangealPIP) joints. Nail pitting or onycholysis were not present. Portableltrasound demonstrated effusion in the same joints identified dur-

ng clinical examination, but no erosions or hyperemia. Bilateraland X-rays were normal. Complete blood count (CBC), renal/liver

unction, erythrocyte sedimentation rate (ESR) and C-reactive pro-ein (CRP) were normal. Screening for antinuclear antibody (ANA),heumatoid factor, anticitrullinated protein antibody (ACPA), HLA-27, parvovirus IgM, and Hepatitis B/C viruses (HBV and HCV)ere negative. HIV load was undetectable, and CD4+ lymphocyte

ount was 672. Treatment for chronic symmetrical seronegativenflammatory arthritis was initiated, using methotrexate (10 mgrally, once-weekly) and folic acid (5 mg orally, once-weekly). Theatient’s CRP was 30 mg/L in December 2011, but she was then

ost to follow-up and did not continue on methotrexate. In March012, she returned with a similar presentation. Portable ultrasoundemonstrated effusion in the same previously affected joints, buto erosions or hyperemia. HIV load was undetectable, and CD4+

ell count was 710. Methotrexate was resumed at a higher dose12.5 mg orally, once-weekly).

In May 2012, no improvement was observed in the patient’sender hands and swollen joint count, and portable ultrasoundgain demonstrated effusion, but no erosions or hyperemia. HIVoad was undetectable, and CD4+ cell count was 871. To control hernflammatory arthritis, the patient, who was PPD-negative and had

normal chest X-ray, started anti-TNF� treatment with etanercept50 mg subcutaneously, once-weekly).

In September 2012, there was no improvement. The patient hadain, morning stiffness, and limitations in daily activities. Portableltrasound showed effusion in the same joints but no erosions oryperemia. She had stable CD4+ counts, undetectable viral load, andas switched to adalimumab (40 mg subcutaneously, bi-monthly).

Two months later, there was ∼70% improvement in symptomsaccording to patient), no morning stiffness, and no limitations inaily activities. Portable ultrasound showed mild effusion in therist joints (bilaterally) and no hyperemia. Also, CRP was normal,D4+ counts were stable, and viral load was undetectable. Adali-umab was continued.

.2. Case 2

A 60-year-old male with type II diabetes mellitus and HIV/HBVo-infection was followed up by the HIV clinic’s Infectiousiseases service. In March 2010, he was started on HAARTomprising atazanavir (300 mg orally, once-daily), Trudava®

emtricitabine/tenofovir; 200 to 300 mg orally, once-daily), anditonavir (100 mg orally, once-daily). In December 2010, he waseferred to the Rheumatology service, presenting with a 1-monthistory of bilateral pain in the elbows, wrists, and small joints ofhe hands, which was accompanied by 10-minute morning stiffnessnd mild limitation of daily activities. No prior joint pain episodesere reported. Apart from being HIV/HBV-positive, he had no his-

ory of viral infection and no personal/family history of psoriasisr connective tissue disease. Examination identified bilateral wristenderness and swelling, as well as the third and fourth PIP joints,ut no elbow abnormalities. No nail changes or skin rashes werebserved. He was given NSAIDs but was subsequently lost to follow-p.

In June 2011, he presented with similar joint discomfort, whichad not responded to NSAIDs. Physical examination and portableltrasound results resembled those previously obtained. Bloodests demonstrated normal CBC, creatinine, and transaminases.

pine 80 (2013) 426–428 427

Moreover, ESR and CRP were normal, and ANA screening, ACPA,and HLA-B27 were negative. Rheumatoid factor was 16 (upper-normal). HIV load was 451 copies/mL, and CD4+ cell count was 256.HBV load was < 12 IU/mL. Inflammatory arthritis treatment wasinitiated (hydroxychloroquine, 200 mg orally, twice-daily; pred-nisolone, 10 mg orally, once-daily for 2 weeks). After 3 months,he had no symptomatic improvement with similar physical andultrasound findings. Following a negative PPD skin test and normalchest radiograph, he was given etanercept (50 mg subcutaneously,once-weekly).

In May 2012, physical and ultrasound results showed markedimprovement, and pain and swelling remained only in his leftwrist, which were managed successfully with Depo-Medrol®

(methylprednisolone, 20 mg intra-articular injection). ESR, CRP,and transaminases were normal. HBV load was undetected, andCD4+ counts and HIV load were stable. Finally, he was seen inSeptember 2012 with significant improvement and no evidenceof synovitis. He requested to discontinue etanercept, but it wasrecommended to maintain therapy until further follow-up.

2.3. Case 3

A 55-year-old male was referred to the Rheumatology servicein March 2011. He had known HIV infection, compensated cir-rhosis secondary to HBV and HCV infection, and end-stage renaldisease on regular hemodialysis. He was receiving HAART com-prised of Truvada® (emtricitabine/tenofovir; 200 to 300 mg orally,once-weekly after hemodialysis), etavirine (200 mg orally, twice-daily), and raltegavir (400 mg orally, twice-daily), as well as calciumcarbonate (600 mg orally, twice-daily) and calcitriol (0.5 mg orally,once-daily). He presented with progressive left-knee pain andswelling for 1 month, but had no history of trauma, fever, skinrashes, back pain, other joint complaints, infection, connective tis-sue disease, or similar episodes. The left knee was warm witheffusion and displayed reduced movement. Crepitus was evidentin both knees, but other joint examinations were unremarkable.

Blood tests demonstrated lymphopenia (white blood cell count:4.4), anemia (hemoglobin levels: 102 g/dL) and thrombocytopenia(platelet count: 125). GFR was < 10. ESR, CRP, AST, ALT, albumin,and bilirubin levels were normal. HIV load was 358 copies/mL, andCD4+ cell count was 130. HBV load was < 15 IU/mL and HCV loadwas 7,566,496 copies/mL. Beta-2-microglobulin levels were high.ANA screening, rheumatoid factor, ACPA, antineutrophil cytoplas-mic antibody, and cryoglobulin tests were negative. Serum uric acidlevels were normal. Synovial fluid aspiration was grossly bloody,with red blood cell count of 75 × 106, white blood cell count of1.222 × 106 (23% polymorphonuclear cells and 38% lymphocytes).Fluid cytology and synovial fluid culture were negative, and syno-vial fluid did not contain crystals. Bilateral knee X-rays indicatedmarked, symmetrical joint space narrowing, subchondral sclero-sis, and erosions, which mainly involved the medial compartmentswithout evidence of chondrocalcinosis. MRI of the left knee sug-gested significant effusion with lateral meniscal tear and partialthickness tear through the anterior cruciate ligament. There wasno evidence of degenerative changes or other abnormalities. TheMRI result suggested traumatic arthritis; however, arthroscopy andsynovial biopsy were not performed because of his comorbidities.Treatment for reactive arthritis was initiated (sulfasalazine, 500 mgorally, twice-daily). A more potent immunosuppressive agent wasnot used due to his hepatitis and end-stage renal disease. Intra-articular Depo-Medrol® was also injected (40 mg).

After 2 months, no improvement had occurred and hydrox-

ychloroquine (200 mg orally, twice-daily) was added. Repeataspiration yielded similar results, and Depo-Medrol® was againadministered (40 mg). In October 2011, there was no treatmentbenefit reported, repeat aspiration showed no improvement, and

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28 H. Almoallim et al. / Joint

tanercept (50 mg subcutaneously, once-weekly) was initiated.wo months later, minimal improvement was observed at follow-p. HIV load, CD4+ cell count, and transaminase levels weretable. He was switched to adalimumab (40 mg subcutaneously, bi-onthly), and 25% improvement occurred after one month. Three

dditional months of adalimumab yielded significant improve-ents in his symptoms and physical findings.After 5 months adalimumab treatment, knee swelling and

evere pain had resolved. HIV load, CD4+ cell count, and transam-nase were stable, but kidney ultrasound revealed a renal mass. In

arch 2012, adalimumab was discontinued.After urological evaluation, no histopathological diagnosis was

ttempted for logistical reasons. However, careful evaluationevealed that the renal mass had been present in a previouslyerformed kidney ultrasound and undiagnosed for years beforerthritis onset. A follow-up ultrasound revealed no change in massize. It was decided that he remain off of adalimumab and be man-ged symptomatically. In subsequent visits in April and September012 the patient complained of knee pain during activity, but thereere no more knee swelling episodes.

. Discussion

With the introduction of HAART, HIV infection became a chronicisease, and improved survival altered the type and frequency ofbserved HIV-associated rheumatic disorders [1]. Thus, identifica-ion of effective treatments for HIV-related arthritis, has become aundamental challenge during HIV management.

Our first patient was initially given methotrexate, which haseen used to treat psoriatic arthritis and psoriasis in HIV patientsndergoing prophylaxis for viral and opportunistic infections [3,4].owever, methotrexate is immunosuppressive, and careful mon-

toring of HIV load and CD4+ counts is necessary [4]. Importantly,ethotrexate cannot be prescribed for all cases since it is con-

raindicated for use during HBV infection, and can trigger HBVeplication/reactivation or accelerate liver disease [5,6].

Our findings agree with case reports that suggested the safetyf anti-TNF� therapy for spondyloarthritis, rheumatoid arthritis, orsoriatic arthritis patients with chronic HBV/HCV infection [7–9].dditionally, while we have demonstrated that anti-TNF� therapyan be safe for HIV-infected patients with rheumatic conditions,he role of TNF� in immunodefense against pathogens cannot begnored [10]. Thus, biologic therapy should be reserved for patients

ith stable HIV loads and CD4+ cell counts > 200/mL. In two caseseported here CD4+ counts were > 200, and the third case had aount of 130. Nevertheless, anti-TNF� therapy was elected for thisnal case due to arthritis persistence and unresponsiveness to con-entional therapies.

Anti-TNF� therapy, infliximab and etanercept, was success-ully used to treat arthritis (psoriatic, reactive, and rheumatoid)n HIV patients within several case reports [11–14]. However, fre-uent polymicrobial infections led to discontinuation of etanercept

n an HIV-positive male with psoriatic arthritis, despite markedmprovement [15], validating the potential repercussions of thisherapy on immune-mediated protection. We did not observe sim-

lar complications, but vigilance is clearly required when usingmmunosuppressive therapies in HIV-infected individuals.

Here, we also demonstrated the efficacy of anti-TNF� ther-py during HIV and HBV/HCV co-infection. All patients had stable

[

pine 80 (2013) 426–428

HIV loads and CD4+ counts, which were monitored throughouttreatment. At last follow-up, the first case was on anti-TNF�therapy (etanercept and adalimumab, respectively) for 5 monthswith significant improvement. In the second case, arthritis wasalmost completely resolved after 12 months of etanercept. Forthe third patient (with HBV/HCV co-infection), HIV load, CD4+ cellcount, HBV/HCV loads, and transamininase levels remained sta-ble. Resolution of persistent arthritis occurred after 5 months ofadalimumab.

In conclusion, anti-TNF� therapies may be considered for treat-ing HIV-associated arthritis when HIV loads and CD4+ counts arestable, even in cases of HBV and/or HCV co-infection. Furtherstudies of the benefit of anti-TNF� agents during HIV-associatedarthritis are necessary for optimizing strategies to combat thedynamic spectrum of rheumatic diseases arising in patients receiv-ing HAART.

Disclosure of interest

The authors declare that they have no conflicts of interest con-cerning this article.

Acknowledgements

This work was funded and supported by Alzaidi Chair ofResearch in Rheumatic Diseases, Umm Alqura University, Makkah,Saudi Arabia.

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