Section 16

Section Editor: G Narsimulu Rheumatology and CTD

206. Refractory Rheumatoid Arthritis 214. Treatment of SLE beyond Steroids Rohini Handa Rathindra Nath Sarkar, Rudrajit Paul 207. Difficulties in Rheumatoid Arthritis 215. Gout Is the Only Enemy That I Do Not Rajan Kumar Wish to Have at My Feet 208. Monoarthritis—A Clinical Dilemma to Internists Anjana Pandey, Ajay Maurya, PK Maheshwari Arup Kumar Kundu, Abhishek Kundu 216. Liver Dysfunction and NAFLD in RA: 209. Oral Targeted Treatments in RA—Update 2021 Is MTX Really a Culprit? Ramakrishna Rao Uppuluri, Sripurna Deepti Challa Kartik Nikhil Balankhe, Rishabh Ramu Nayak, Pulin Kumar Gupta 210. Biosimilars: Bane or Boon for India 217. Sexual Dysfunction in Rheumatic Diseases Durga Prasanna Misra, Pallavi Patro, Vikas Agarwal Vinod Ravindran 211. An Approach to Vasculitis 218. Interpretation of Common Investigations Packiamary Jerome in Rheumatology 212. How to Manage DMARDs Failure in RA? Renu Saigal, Amit Kansal, Vikram Raj Jain N Subramanian 213. IgG4-related Disease Harpreet Singh, Somdatta Giri, Anju Arya

MU-206 (Sec-16).indd 1321 29-01-2021 15:25:29 MU-206 (Sec-16).indd 1322 29-01-2021 15:25:30 CHAPTER

206 Refractory Rheumatoid Arthritis

Rohini Handa

Abstract A sizeable number of patients with rheumatoid arthritis (RA) are unable to attain low disease activity or remission despite treatment. These difficult to treat (D2T) patients are labeled as refractory RA. The troika of D2T RA, as outlined by the European League against Rheumatism, comprises of treatment failure history, presence of active/symptomatic disease, and clinical perception. The approach to refractory RA is evolving.

Introduction differently. The analogy that I often use is “pyrexia or fever of unknown origin” (PUO/FUO) that was initially Rheumatoid arthritis (RA) is the commonest inflammatory defined as a condition in which the core body temperature polyarthritis seen in clinical practice. Current management is >38.3°C for a period of three weeks or more, with no paradigms use a “treat to target” stratagem to achieve diagnosis reached after 1 week of “inpatient investigation.” tight disease control. The conventional synthetic disease The quantum and extent of investigations were not spelt modifying anti-rheumatic drugs (csDMARDs) led out. Also, modern day health care has moved away from by methotrexate form the initial treatment. A better hospitalization for investigations. The revised definition of understanding of the disease, pathobiology has led to the PUO-“persistent fever that remains undiagnosed despite development of several targeted treatments, which are 1 week of hospital evaluation or three outpatient visits” broadly divided into two categories: biologic DMARDs also suffers from lack of specificity. Much in the same (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). way, the definition of refractory RA continues to elude Despite tremendous advances in disease assessment, consensus. and an ever expanding treatment armamentarium, a Simply put, refractory RA is disease that continues to significant proportion of patients are unable to achieve be active despite adequate treatment for sufficient time. optimal disease control. This group of “refractory” patients The lack of uniformity stems from the fact that refractory poses a challenge to the immunologists from a mechanistic RA has three dimensions: disease activity, adequacy of angle, to rheumatologists from the perspective of disease treatment, and time. The concept of disease activity is a definition, and to all clinicians from a treatment viewpoint. quantitative target with reasonably well defined variables. This chapter outlines the approach to refractory RA from a Validated indices like simplified disease activity index clinical standpoint. (SDAI) and clinical disease activity index (CDAI) are available and widely used in rheumatology clinics. Their Definition of Refractory RA use is overtaking the use of DAS 28 (disease activity score The definition of refractory RA is imprecise as different 28). A detailed exposition of various disease activity authors, in absence of a consensus, have defined it measures is beyond the scope of this chapter. Briefly, SDAI

MU-206 (Sec-16).indd 1323 29-01-2021 15:25:30 1324 SECTION 16 Rheumatology and CTD

TABLE 1 Instruments to measure disease activity in RA

Score range Remission Low Moderate High DAS28 0–9.4 <2.6 <3.2 >3.2 and <5.1 >5.1 SDAI 0.1–86 <3.3 <11 >11 and <26 >26 CDAI 0–76 <2.8 <10 >10 and <22 >22 CDAI, clinical disease activity index; DAS, disease activity score; SDAI, simplified disease activity index

TABLE 2 American College of Rheumatology/European League Against Rheumatism definitions of remission in RA

For clinical trials For clinical practice Boolean-based definition Boolean-based definition At any time point, patient must satisfy all of the following: At any time point, patient must satisfy all of the following: zz Tender joint count ≤1 zz Tender joint count ≤1 zz Swollen joint count ≤1 zz Swollen joint count ≤1 zz C reactive protein ≤1 mg/dL zz Patient global assessment ≤1 (on a 0–10 scale) zz Patient global assessment ≤1 (on a 0–10 scale) Index-based definition Index-based definition At any time point, patient must have a Simplified Disease Activity At any time point, patient must have a Clinical Disease Activity Index Index score of ≤3.3 score of ≤2.8

is simple numerical summation of swollen joint count most 3 months after the start of treatment, or the target (SJC)-28 joints, tender joint count (TJC)-28 joints, CRP in has not been reached by 6 months, therapy should be mg/dL (range 0.1–10), patient’s global disease activity on a adjusted. 10-cm visual analogue scale (VAS) and physician’s global It is the third component of the definition—adequate assessment on a 10-cm VAS. The CDAI excludes CRP. DAS treatment—that is a matter of debate. Recent clinical trials 28 requires four simple inputs: 28 TJC, 28 SJC, ESR, and define refractory RA as “moderately to severely active general health (GH) assessment by the patient on a VAS RA (≥6 tender joints of 68 joints examined, ≥6 swollen from 0 to 100. The formula used is: DAS 28 = 0.56√TJC joints of 66 joints examined, and a serum CRP level ≥3 + 0.28√SJC + 0.7 ln ESR + 0.014 GH. Online calculators mg per liter) and patients must have previously received and apps are available for calculation. The cut offs are one or more TNF inhibitors and discontinued treatment mentioned in Table 1. The goal of treatment is remission because of an insufficient response after 3 months or more (Table 2),1 failing which low disease activity (LDA) is an or because of unacceptable side effects.”5 Other authors acceptable alternative. define refractory RA as patients who have experienced The second operational component—time taken to three treatment courses (with at least one biological) over achieve LDA/remission—has undergone a sea change. a minimum of 18 months since diagnosis without reaching Older publications talk about early disease as a disease the treatment goal of low disease activity or remission.6 duration of 2 years. Current recommendations like To make matters complex, some authors have European League against Rheumatism (EULAR) and proposed that non-responders be classified into “primary” American College of Rheumatology talk about early RA and “secondary” non-responders. The latter, after the as a disease duration less than 6 months.2,3 They also initial response to the drug, stop responding after a emphasize that clinicians should aim for clinical remission variable period of time. In some of these, anti-drug (ACR-EULAR criteria) or at least low disease activity within antibodies (ADA) to the biologics may be responsible 6 months (of which about 80% improvement of disease for the secondary non-response. This has been termed activity should be within 3 months of starting treatment).4 “pharmacokinetic refractoriness” to differentiate it from It is recommended that if there is no improvement by at intrinsic refractoriness in the primary non-responders.7

MU-206 (Sec-16).indd 1324 29-01-2021 15:25:30 Refractory Rheumatoid Arthritis CHAPTER 206 1325

It is to be noted that not all secondary non-response are How Common is Refractory RA? due to ADA. Also, ADA are seen with biologics, which are Biologics, contrary to the popular perception of many foreign proteins and not with csDMARDs or tsDMARDs internists, do not work for all patients. As many as one- like JAK inhibitors. This group proposes that refractory RA third of patients treated with TNF inhibitors exhibits be defined by resistance to multiple therapeutic drugs with inadequate response or intolerance. In general, the efficacy different structures and mechanisms of action—inefficacy of biologics in patients failing methotrexate is given by the of optimal dose methotrexate and at least two biologics broad thumb rule of ACR-20/-50/-70 of 60/40/20%. That with different mechanism of action.7 They suggest that is, ACR 20 response is seen in 60% of such patients, ACR multiple within-class bDMARD resistance (as with TNFi 50 response in 40% patients while ACR 70 response is seen cycling) be excluded from the ambit of refractory RA and in 20% patients. In patients failing anti-TNFs, the ACR-20/- a patient failing MTX and one TNFi needs to fail another 50/-70 drop further to 50/25/12% respectively. non-TNF before being labeled as refractory.7 The time The prevalence estimates of refractory RA vary period of 6 months incorporated in most guidelines between 6% and 21% depending on threshold and study for achieving LDA with treatment would translate into population.9 Obviously, referral centers would be expected a period of at least 18–24 months for a patient to fail a to encounter more refractory patients. Risk factors for minimum of two classes of bDMARDs.7 It is pertinent to refractory RA include treatment delay, baseline disease point out that not incorporated in this working definition activity and function, female gender, smoking, obesity, is the place of JAKi. and lower socioeconomic status.9

Can the Same Definition of Refractory RA How should Overdiagnosis of Refractory be Applied to Low Resource Settings? RA be Avoided? The uptake of targeted treatments in resource constrained A label of refractory RA should be applied after care­ countries is very low. This is especially true of bDMARDs. ful consideration (Fig. 1). Overclassification and With little insurance or government support, the bulk of misclassification may result in inappropriate therapy treatment cost is borne by the patients themselves. The escalation. Coexistence of fibromyalgia may lead to average duration of biologic use is less than a year.8 The disproportionate increase in patient reported symptoms indirect implication of this is that definitions of refractory and distort disease assessment. Secondary damage and RA, as applicable in the west, cannot be extrapolated to osteoarthritis can also lead to higher disease activity countries like India. Biologic use, to begin with, is quite less scores and apparent refractoriness. and switching or swapping of biologics even lesser. From a practical standpoint, refractory RA in India can be defined as patients who continue to have active disease despite Treatment of Refractory RA a combination of csDMARDs plus low dose steroids The treatment of refractory RA revolves around the (prednisolone <7.5 mg daily). Implicit in this statement use of targeted treatments—bDMARDs or tsDMARDs. is optimal dosing of drugs: subcutaneous methotrexate Patients failing one drug are switched to another (15–25 mg weekly) along with hydroxychloroquine (200– agent. Switching to an alternate agent with same MOA 400 mg daily) and leflunomide (20 mg daily). In clinical (intra-class switching) has been called “cycling” and settings like women of child bearing age, sulfasalazine switching to agents with a different MOA has been (2–3 gm daily) can be used in place of leflunomide. termed “swapping.”10 These terms are by no means The availability of low cost, generic JAK inhibitors in universally accepted. There is no consensus on sequence the near future is likely to change the whole equation. of switching. Physician familiarity, patient preference, Biologic DMARDs and biosimilars are expensive, given the and drug characteristics like availability, cost, safety, and complexities of manufacture. However, tsDMARDs like efficacy are some of the factors to be considered. Of the ten tofacitinib and baricitinib are not as difficult or expensive bDMARDs available worldwide, six are available in India to produce. Their availability would necessitate a change (Table 3). The tsDMARDs in RA are the JAK inhibitors. in the definition of refractory RA in India. Two of the four JAKi are available for use in India (Table 4).

MU-206 (Sec-16).indd 1325 29-01-2021 15:25:30 1326 SECTION 16 Rheumatology and CTD

Fig. 1: Pathway to labeling refractory RA csDMARDS, conventional synthetic DMARDs like methotrexate, hydroxychloroquine, leflunomide and sulfasalazine; MCRH, multicentric reticulohistiocytosis; PsA, psoriatic arthritis; SpA, spondyloarthritis

TABLE 3 Biologics available in India

Biologic Target Route of administration Usual adult dose Infliximab TNF Intravenous In conjunction with methotrexate, 3 mg/kg at 0, 2, and 6 weeks, then every 8 weeks Etanercept TNF Subcutaneous 50 mg weekly Adalimumab TNF Subcutaneous 40 mg every other week Golimumab TNF Subcutaneous 50 mg once a month Tocilizumab IL-6R Intravenous and subcutaneous Intravenous: Recommended starting dose is 4 mg/kg every 4 weeks followed by an increase to 8 mg/kg every 4 weeks based on clinical response. Subcutaneous: 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Rituximab CD 20 on B cells Intravenous The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks IL-6R, interleukin 6 receptor; TNF, tumor necrosis factor N.B.: Abatacept, Anakinra, Sarilumab, and Certolizumab are not available in India.

Recommendations from professional bodies like APLAR TABLE 4 Targeted synthetic (ts) DMARDs available in India and EULAR do not spell out any particular sequence to Agent JAKs targeted Oral dose follow.2,11 It is to be pointed out that csDMARDs can be Tofacitinib JAK1, JAK2, JAK3 5 mg BD combined. However, combinations of biologics or JAKi or Baricitinib JAK1, JAK2 2–4 mg OD biologic-JAKi combination are not recommended for fear JAK, Janus kinas of intense immunosuppression (Flowchart 1). N.B.: Upadacitinib and Peficitinib are not available in India

MU-206 (Sec-16).indd 1326 29-01-2021 15:25:31 Refractory Rheumatoid Arthritis CHAPTER 206 1327

Flowchart 1: Treatment of refractory RA References . 1 Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials. Ann Rheum Dis. 2011;70:404-13. . 2 Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685-99. . 3 Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-25. . 4 Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-38. 5. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-52. . 6 Unger M, Alasti F, Supp G, et al. The good, the bad and the ugly—refractory rheumatoid arthritis in 2016 [abstract]. Arthritis Rheumatol. 2016;68(Suppl 10). Available from https://acrabstracts. org/abstract/the-good-the-bad-and-the-ugly-refractory- rheumatoid-arthritisin-2016/ [Accessed June 4, 2020]. 7. Buch MH. Defining refractory rheumatoid arthritis. Ann Rheum Dis. 2018;77:966-9. . 8 Shobha V, Rao V, Desai AM, et al. Prescribing patterns and safety of biologics in immune-mediated rheumatic diseases: Karnataka biologics cohort study group experience. Indian J Rheumatol. 2019;14:17-20. . 9 Melville AR, Kearsley-Fleet L, Buch MH, et al. Understanding refractory rheumatoid arthritis: implications for a therapeutic Conclusion approach. Drugs. 2020;80:849-57. 10. Favalli EG, Biggioggero M, Marchesoni A, et al. Survival on treatment Refractory RA represents an area of unmet need in the arena with second-line biologic therapy: a cohort study comparing of rheumatology. The definition itself continues to evolve cycling and swap strategies [published correction appears in with the expansion of DMARD classes—from csDMARDs Rheumatology (Oxford). 2015;54(7):1337]. Rheumatology (Oxford). through bDMARDs to, now, tsDMARDs. Ensuring adherence 2014;53:1664-8. to treatment and excluding the contribution of damage/ 11. Lau CS, Chia F, Dans L, et al. 2018 update of the APLAR degeneration to disease activity assessment are important recommendations for treatment of rheumatoid arthritis. Int J to avoid misclassification as refractory RA. Biologics and Rheum Dis. 2019;22:357-75. tsDMARDs are used to treat refractory disease. In absence of biomarkers, the sequencing of bDMARDs and tsDMARDs at present is empirical. Hopefully, the advent of precision medicine in future would permit clinicians to move away from “generic” protocols to “individualized” protocols in the disease segment that is refractory RA!

MU-206 (Sec-16).indd 1327 29-01-2021 15:25:32 CHAPTER

Difficulties in 207 Rheumatoid Arthritis

Rajan Kumar

Abstract Rheumatoid arthritis is not an uncommon arthritis. There is overlap in the markers and clinical features. One should try to decipher the diagnosis with their markers and this will help in deciding treatment. By identifying the signs of flare ups and treatment failure we can plan treatment with algorithm.

Introduction symptoms. There is an involvement of smaller joints in hand symmetrically, particularly involving proximal Rheumatoid arthritis marked by synovitis in small joints, interphalangeal (PIP) joints, metacarpophalangeal (MCP) acute phase reactants, and biomarkers. Sometimes joints with positive squeeze sign and loss of guttering in biomarkers are absent but small joints and acute phase between MCP joints, wrist, elbow, shoulder, knee, and reactants are present diagnosis depend on clinical judgment and wait for others markers to evolve but feet with small joints. You can diagnose it easily if there is if treated early, then long-term complications of join more than three symmetrical joints involvement in hand deformities and disabilities can be decreased. In presence of PIP, MCP along acute phase reactants and autoimmune of other biomarkers along with specific for Rheumatoid markers in the form of rheumatoid factor (RF) and anti- arthritis, subtle judgment will help in classifying disease cyclic citrullinated (ACC) antibodies. When this is the syndrome. It is also pertinent to identify flare ups of disease situation, things are very easy. But the problem starts and failure of treatment so that we can achieve remission. when: Finally treat to target will help in prolonging life. „„ You have autoimmune markers but no clinical features Rheumatoid arthritis is one of the most common or synovitis or joint pain. arthritis. Every clinician might have got an opportunity to „„ Clinical features of synovitis and evidence of treat it. They might have encountered some difficulties in symmetrical small joint arthritis with no autoimmune the management, particularly in: markers. „„ Diagnosis How to predict the diagnosis of rheumatoid arthritis in „„ Treatment these two conditions. To diagnose rheumatoid arthritis when all clinical sings Firstly, with autoimmune markers without evidence of and markers are present is not a difficult task. Patients synovitis: classically come with the complains of pain and early „„ RF only morning stiffness lasting for more than an hour and for „„ Both RF and anti-cyclic citrullinated protein (ACCP) more than 6 weeks with systemic symptoms or no systemic antibody

MU-207.indd 1328 29-01-2021 15:25:23 Difficulties in Rheumatoid Arthritis CHAPTER 207 1329

TABLE 1 There different studies which shows the predictive value

Nielen et al (2004) RF-IgM, anti-CCP2 PPV of up to 100% for RA diagnosis within 5 years Deane et al. (2010) RF isotypes, anti-CCP2 Anti-CCP and/or two or RF isotypes positive with >96% PPV for RA compared to two control groups Ramos-Remus et al. (2015) RF, anti-CCP2 RF and anti-CCP positivity at baseline with PPV 64% for RA within 5 years; anti- CCP alone with PPV of 58% Sokolove et al. (2012) RF, ACPA array, variety of A set of ACPAs and cytokines was 58% sensitive and 87% specific for identifying cytokines and chemokines a sample ≤2 years before diagnosis ACPA, anti-citrullinated protein antibody; CCP, cyclic citrullinated protein/peptide; PPV, positive predictive value; RA, rheumatoid arthritis; RF, rheumatoid factor.

We have to take the account that genetic factors (e.g., Now second situation is that when there is a synovitis the shared epitopes) are environmental factors (smoking with typical joint involvement but no autoimmune and high body mass index) and RF isotypes particularly markers, then how we can diagnose RA. We need; high-titter IgM-RF and IgA-RF presence will favor the History of more than 6 weeks of morning stiffness, future development of rheumatoid arthritis. symmetric arthritis involving PIP, MCP joints, ACCP are of three types on the basis of method of subcutaneous nodules, and the deformities characteristic antigen used anti-CCP1 (ELISA), anti-CCP2 (tested with of RA. synthetic peptides), anti-CCP3 (tested with synthetic There are other disorders but having similar peptides), of theses, presence of anti-CCP2 has more presentation but with presence of rashes, dry mouth and predictive value for the future development of RA. dry eyes, Raynaud’s phenomenon, myositis, or nephritis, With only presence of autoimmune markers, it takes involvement typical organs and by various autoantibodies 3–5 years to develop from the stage of autoimmunity to not seen in RA may clinch the diagnosis, for example. autoimmune disease. But it depends on: Systemic lupus erythematosus (SLE), Sjögren’s syndrome, „„ Levels of autoantibodies Dermatomyositis (DM), Sarcoidosis, Psoriatic arthritis, „„ Number of ACCPAs Overlap syndromes such as mixed connective tissue „„ Presence of both ACCPAs and RF disease. „„ Additional biomarkers such as cytokines and Some of inflammatory arthritis (IA) which do not fit chemokines in any of the classical syndrome, then we mark them as „„ Other factors such as environmental exposures and unclassified arthritis. Now even in these situations we symptoms can work up diagnosis in the favor of RA with anti-CCP There different studies which show the predictive presence, unconventional serologic findings (e.g., IgA type values have been discussed in the Table 1. We need to develop an effective tools to measure rheumatoid factor, pyridinoline), and MRI-proven early the response of successful preventive interventions in joint damage, synovial thickening, marrow edema, and preclinical RA (window of opportunity), when challenged erosions. with disease-modifying anti-rheumatic drug (DMARD) or There are situations in which inflammatory arthritis is other effective treatment in this window of opportunity. present with: Rituximab and other pharmacologic agents, including „„ RF with ANA (anti-nuclear antibodies) with erosions, hydroxychloroquine, abatacept, and atorvastatin were the diagnosis goes the favors RA. tried in various trials for prevention in various trials „„ Without erosions and clinical features suggestive of without much success. SLE or but with ANA and ACCP antibody clinch the The best time to treat is when patients having arthralgia diagnosis of rheumatoid arthritis. and synovitis. Treatment within first 3 months of onset of „„ But patients having features of both RA and SLE with the disease can lead to long-term remission, the so-called presence of RF and ANA will favor the diagnosis of window of opportunity period. overlap syndrome.

MU-207.indd 1329 29-01-2021 15:25:23 1330 SECTION 16 Rheumatology and CTD

„„ With RF, ANA, and Un RNP and IA, the diagnosis will [cs]), biologic (b), or targeted synthetic (ts) DMARD in go in favor of mixed connective tissue disease. maximally tolerated doses within the usual therapeutic Two of clinical variants of RA poses some difficulty. range. The first one is the presentation with monoarthritis. „„ Continued erosion despite patient on treatment even Mono arthritis with involvement a large joint, such with no pain. as the wrist, knee, shoulder, hip, or ankle, may be the „„ Requirement of 5–7.5 mg prednisone or larger doses to sole manifestation of RA, but how to predict RA in these maintain achievement after 3 months of DMARD use. patients. One should investigate the patients, for the „„ Multiple courses of treatment with glucocorticoids for presence of the RF and ACCP antibodies. the treatment of recurrent disease flares in patients If they are there, then wait for typical disease features whose DMARD doses have been increased to the to evolve. Usually it takes days to several weeks to develop maximally tolerated. polyarthritis from monoarthritis till then we should treat Flares may be with: them as monoarthritis with NSAIDs and local steroid „„ Single or few affected joints treated them with NSAIDs injection if required. for few days and local steroid injection in joint if To rule out that monoarthritis of large joints are required. due to spondyloarthritis, MRI will help to find out „„ Widespread flares with multiple joints with need low more destructive change (synovial thickening, marrow doses of steroid. edema, and erosions) in the patients with RA and but „„ Severe flares, particularly those associated with enthesopathy in the patients with spondyloarthropathy systemic manifestations and life-threatening than in the patients with undifferentiated arthritis. conditions, such as rheumatoid vasculitis will need Second one is the presentation with Palindromic intravenous pulse methylprednisolone in high doses rheumatism in this condition, episodes of joint with long use of steroid. inflammation sequentially affecting one to several joint „„ Flaring frequently or severely will need escalation areas for hours to days, with the symptom-free periods of doses of continued DMARD and/or addition of that may last from days to months. Patients with anti-CCP another DMARD of same group of different groups. antibodies appear more likely to progress to definite RA later on. It has to be differentiated from the migratory DMARDS are selected in step ladder approach: arthritis. „„ MTX (methotrexate) So the key points for predicting RA we will need „„ HCQ/SSZ (hydroxychloroquine/sulfasalazine) „„ to focus on sex, age, morning stiffness, localization of HCQ + SSZ + MTX, i.e., triple therapy Patients resistant to triple therapy can be treated symptoms, tender and swollen joint counts, C-reactive with MTX plus leflunomide (LEF) please note that protein, rheumatoid factor positivity, and presence of this may require closer monitoring (e.g., monthly with ACCP antibodies. There are scoring systems to predict the aminotransferase testing) for hepatotoxicity, given the development of RA. increased risk of hepatotoxicity in some but not in the We face some difficulties in treatment also. most studies, including reports of fatal liver failure. Firstly, in the choice of treatment, secondly detecting „„ MTX + TNF blocker (tumor necrosis factor) ETN the failure of DMARD and lastly managing the flare ups. (Etanercept) or ADA (Adalimumab) We usually start treating with NSAIDs (nonsteroidal „„ Methotrexate plus Rituximab equivalent to TNF anti-inflammatory drugs), steroid and CsDMARDs blocker combination (conventional synthetic DMARD). But sometimes it does „„ Rituximab is effective alone in the patient intolerant not give the desired results. Treat to the target is the rule with MTX of thumb. „„ MTX + tsDMARD (tofacitinib) Failure can be defined as: „„ LEF (leflunomide) alternative to MTX „„ Not able to remission with the target achievement „„ In pregnancy TNF blocker can be used alone within 3–6 months of continuous use of DMARDS „„ LEF if there is moderate renal dysfunction/nontolerant irrespective of nonbiologic (conventional synthetic to MTX

MU-207.indd 1330 29-01-2021 15:25:23 Difficulties in Rheumatoid Arthritis CHAPTER 207 1331

„„ MTX + Abatacept 3. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism „„ MTX + IL 6 inhibitors tocilizumab and sarilumab Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-24. Patient needs months and years of continued therapy 4. Finckh A, Liang MH. Anti-cyclic citrullinated peptide antibodies in for adequate response. the diagnosis of rheumatoid arthritis: bayes clears the haze. Ann Downregulating the DMARDs only after 1 year of Intern Med. 2007;146(11):816-7. sustained response otherwise flare ups are very much 5. Klareskog L, Catrina AI, Paget S, et al. Rheumatoid arthritis. Lancet. common. 2009;373(9664):659. . 6 Knevel R, Schoels M, Huizinga TW, et al. Current evidence for a Some patients remain in remission on reduced doses strategic approach to the management of rheumatoid arthritis but decision to discontinue treat remain debatable and with disease-modifying antirheumatic drugs: a systematic controversial. literature review informing the EULAR recommendations for The best candidates for achieving a drug-free remission the management of rheumatoid arthritis. Ann Rheum Dis. appear to be the patients who have a short duration of 2010;69(6):987-94. 7. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic symptoms when treatment is started, are of the male sex, accuracy of anti-cyclic citrullinated peptide antibody and have an absence of RF and ACPAs, have received early rheumatoid factor for rheumatoid arthritis. Ann Intern Med. intensive therapy, and have achieved a deep remission 2007;146(11):797-808. based upon composite scores of disease activity. 8. Pincus T, Callahan LF. How many types of patients meet classification criteria for rheumatoid arthritis? J Rheumatol. 1994;21:1385-9. . 9 Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 Conclusion American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in Autoimmune biomarker testing and clinical features allow the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). us to rightly interpret the diagnosis. And knowing the failure, 2012;64(5):625-39. remission, and flare up sign and symptoms will lead to proper 10. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis use of different demands in algorithm. to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631-7. 11. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations Bibliography for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. . 1 Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis 2010;69(6):964-75. classification criteria: an American College of Rheumatology/ 12. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations European League Against Rheumatism collaborative initiative. for the management of rheumatoid arthritis with synthetic and Arthritis Rheum. 2010;62(9):2569-81. biological disease-modifying antirheumatic drugs: 2013 update. . 2 Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis Ann Rheum Dis. 2014;73(3):492-509. classification criteria: an American College of Rheumatology/ 13. Whiting PF, Smidt N, Sterne JA, et al. Systematic review: accuracy European League Against Rheumatism collaborative initiative. Ann of anti-citrullinated peptide antibodies for diagnosing rheumatoid Rheum Dis. 2010;69(9):1580-8. arthritis. Ann Intern Med. 2010;152(7):456-64.

MU-207.indd 1331 29-01-2021 15:25:23 CHAPTER

Monoarthritis—A Clinical 208 Dilemma to Internists

Arup Kumar Kundu, Abhishek Kundu

Abstract The monoarthritis can either be acute or chronic, and may be either inflammatory or non-inflammatory. A detailed history and meticulous physical examination are essential in determining the etiology of arthritis. Diagnosis of monoarthritis is always a challenge to the internist. The common causes of acute monoarthritis are gout (crystal-induced arthritis), trauma, and infection, while that of chronic monoarthritis are osteoarthritis, tuberculous arthritis, gout, or spondyloarthropathy. So-called polyarticular diseases like systemic lupus erythematosus, rheumatoid arthritis may start as monoarthritis. If one investigation has to be done, it is synovial fluid examination, while synovial biopsy specimen is often examined for etiological agents in Lyme disease, gonococci, tuberculosis, or chlamydia infection. Light microscopy may identify gout crystals, but polarized microscopy is always preferred. Review of systemic diseases like sarcoidosis, malignancy, etc. is important because they may be complicated by monoarthritis.

Introduction Complete blood count, bleeding and clotting time, ESR, C-reactive protein (CRP), serum uric acid, rheumatoid Monoarthritis is defined as inflammation of one joint at a factor and antinuclear factor, urine analysis, and blood or time, while acute monoarthritis is acute inflammation of a urine culture should be performed, as and when necessary. single previously healthy joint, typically developing within a few days. Chronic monoarthritis is the inflammatory Blood culture should be done if clinical suspicion of arthritis of a single joint that persists for more than 6 weeks. septic arthritis is very high. Many a time, examination of Acute monoarthritis may be the initial manifestation joint fluid is essential in making a definitive diagnosis. of many of the rheumatological disorders or systemic Leukocyte counts may vary widely in septic and sterile connective tissue diseases. The most common causes of synovial fluids, and should be interpreted cautiously acute monoarthritis are crystal arthropathy (i.e., gout in an open mind. The joints, such as hip or sacroiliac and pseudogout), trauma, and infection.1 The patient of joints, are difficult to aspirate and very often computed monoarthritis should undergo careful and meticulous tomography or ultrasound-guided arthrocentesis helps to history, rational physical examination, and selected draw synovial fluid from these types of deep-seated joints. laboratory tests. Acute monoarthritis (red-hot joint) When an infection is suspected, culture and Gram staining represents a rheumatologic emergency and requires rapid of the synovial fluid should be performed and antibiotics assessment, diagnosis, and aggressive treatment, since should be started empirically. Light microscopy may an untreated septic arthritis may lead to irreversible joint identify gout crystals, but polarized microscopy is always damage and resultant disability. In spite of the intensive preferred. If, however, the diagnosis is yet to be reached, investigations, at times, no clear diagnosis can be made. radiographic studies (such as technetium bone scan,

MU-208.indd 1332 29-01-2021 15:25:12 Monoarthritis—A Clinical Dilemma to Internists CHAPTER 208 1333

computed tomographic scanning or magnetic resonance synovial fluid, articular cartilage, joint capsule and juxta- imaging) are performed in selected cases (such as internal articular bone. Non-articular (periarticular) structures derangement or osteonecrosis), and even, invasive include ligaments, bone, tendons, bursa, muscle, fascia, procedures such as arthroscopy and synovial biopsy may nerve, and overlying skin. “Arthritis” results in stiffness, be necessary to clinch the final diagnosis in undiagnosed reduced range of motion, and pain of the involved joint chronic monoarthritis. The other systems should be during normal use, which is most noticeable in the evaluated because, many a time, thalassemia, sarcoidosis, morning, improves with motion, and may be associated sickle cell anemia, or hemophilia may be a cause for with systemic symptoms (i.e., malaise or fever). Joint monoarthritis. pain due to mechanical factors (non-articular) usually improves with rest, deteriorates with activities and is Monoarthritis: An Overview not associated with systemic symptoms. In differential Monoarthritis represents a diagnostic challenge to diagnosis (D/D) of musculoskeletal pain diffuse bone every physician. The doctor first decides the anatomical diseases like multiple myeloma, metabolic bone disease basis of pain (i.e., articular vs. non-articular). Joint pain or multifocal osteomyelitis should be considered. can be the result of abnormalities in the joint itself, Possible causes of acute and chronic monoarthritis adjacent bone, surrounding ligaments, tendons, bursa, have been elaborated in Table 1.2,3 Arthritis may be or soft tissues. Articular structures consist of synovium, monoarthritis (single joint), oligo- or pauciarthritis (2–4

TABLE 1 Etiology of monoarthritis2,3

Common causes zz Trauma zz Crystals—monosodium urate (MSU), calcium pyrophosphate dehydrate (CPPD), hydroxyapatite, calcium oxalate zz Septic arthritis (non-gonococcal, gonococcal) zz Hemarthrosis (trauma and/or coagulation disorder) zz Avascular necrosis of bone (i.e., osteonecrosis) zz Internal derangement (e.g., meniscus tear, cartilage debris) zz Osteoarthritis zz Osteomyelitis zz Overuse (e.g., in a pre-existing osteoarthritic joint) zz Monoarticular flare of oligoarthritis or polyarthritis

Less frequent causes zz Malignancy of bone zz Hemoglobinopathies (i.e., sickle cell anemia) zz Enteropathic arthritis (e.g., Crohn’s disease, ulcerative colitis) zz Sarcoidosis zz Loose bodies within joint zz Infections—mycobacteria, fungi zz Leukemia zz Rheumatoid arthritis (RA—palindromic), reactive arthritis (ReA), psoriatic arthropathy (PsA), juvenile idiopathic arthritis (JIA) zz Vasculitis

Rare causes zz Hypertrophic pulmonary osteoarthropathy (developing from bronchogenic carcinoma) zz Foreign body (e.g., plant thorn) zz Pigmented villonodular synovitis zz Amyloidosis zz Lyme disease zz Familial Mediterranean fever zz Relapsing polychondritis zz Charcot joint zz Behçet’s syndrome zz Synovial chondromatosis/sarcoma/synovial metastasis

MU-208.indd 1333 29-01-2021 15:25:17 1334 SECTION 16 Rheumatology and CTD

TABLE 2 Working classification according to onset and duration2,3

Acute (duration <6 weeks) Chronic (duration >6 weeks) zz Infection (bacterial, mycobacterial, fungal, or viral; Lyme disease) zz Infection (tuberculosis, brucellosis, fungal) zz Crystals (MSU, CPPD, calcium hydroxyapatite, calcium oxalate) zz Crystals (MSU, CPPD, etc.) zz Trauma (fracture or internal derangement) zz Osteoarthritis (commonly knee joint) zz Monoarticular presentation of a polyarticular disease (i.e., zz Sarcoidosis (e.g., ankle joint) immunoinflammatory—RA, SpA, PsA, IBD, or SLE) zz Osteoarthritis (knee, hip, or 1st MCP) zz Seronegative SpA and chronic ReA zz Hemarthrosis (trauma, coagulation abnormality) zz Pigmented villonodular synovitis (PVNS) zz Ischemic (avascular) necrosis—of hip from SLE or corticosteroid zz Synovial chondromatosis/sarcoma therapy zz Tumor (metastasis, PVNS) zz Foreign body (plant thorn) synovitis zz Foreign body synovitis (wood fragments, plant thorn) zz Charcot (neuropathic) joint (e.g., leprosy, syringomyelia) zz Systemic diseases presenting as monoarthritis (e.g., acromegaly zz Monoarticular presentation of a polyarticular disease (i.e., RA, producing pseudogout) SpA, PsA) Summary of working classification: Acute monoarthritis—Septic, crystals, traumatic, SpA (especially, ReA) Chronic monoarthritis—Osteoarthritis, crystals, SpA (especially chronic ReA), tuberculous IBD, inflammatory bowel disease; MCP, metacarpophalangeal; PsA, psoriatic arthropathy; RA, rheumatoid arthritis; ReA, reactive arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthropathy

joints) and polyarthritis (≥5 joints). Monoarthritis can „„ Elderly diabetic lady having knee replacement 1 year either be acute (duration <6 weeks) or chronic (duration back where the knee is presently acutely swollen, hot, >6 weeks), and may be either inflammatory or non- tender with high pyrexia, and toxicity indicates septic inflammatory (Table 2).2,3 arthritis. „„ Young male with acute knee pain, plus history of Approach to Evaluation of Monoarthritis neck and back pain will have a probable diagnosis of The first and most important steps in evaluation are ankylosing spondylitis (SpA). thorough history taking. Onset of symptoms, history Investigations—If one investigation has to be done, of fever, recent travel, IV drug or alcohol abuse, sexual it is synovial fluid examination, and the fluid should be exposure, tick or insect bite, diarrhea, urinary tract examined for infection, trauma, gardening (e.g., plant thorn synovitis), „„ Gram stain or pre-existing systemic disease should be enquired. „„ Routine culture History of drug therapy (e.g., diuretics in gout), skin rash, „„ Total and differential WBC count oral or genital ulcers, and prolonged bleeding should „„ Crystals under polarized light microscope. be taken into account (Table 3). Next task is to start It is simple, safe, and a very easy bedside procedure thorough physical examination where a physician has without any complication, if performed aseptically. to differentiate articular from non-articular disease (see Synovial biopsy is done in selective cases (e.g., tuberculous previous paragraph). Deep-seated joints like hip and synovitis) by needle aspiration or arthroscopy. Recently, sacroiliac joints are difficult to evaluate. Consider the D/D by polymerase chain reaction and immunoelectron of single “red-hot joint” (Table 4). microscopy, synovial biopsy specimen is examined Clue for initial clinical observation (ideal examples): for etiological agents in Lyme disease, gonococci, or „„ Middle-aged male with red, hot, tender, and swollen chlamydia infection. Other common tests done are blood 1st metatarsophalangeal joint points toward gout. for total and differential count, blood and urine culture,

MU-208.indd 1334 29-01-2021 15:25:17 Monoarthritis—A Clinical Dilemma to Internists CHAPTER 208 1335

TABLE 3 Clinical clues in the history and physical examination

History and clinical findings Probable diagnosis Sudden onset of pain developing within seconds or minutes Trauma, fracture, internal derangement Onset of pain arising over several hours or within days Infection, crystal arthropathy, any inflammatory arthritis Onset of pain developing over days to weeks Indolent infection, osteoarthritis, infiltrative disease, tumor (synovium/bone) Young adult with history of promiscuous sex and migratory arthritis Gonococcal arthritis History of diabetes mellitus, immunosuppression, bacterial endocarditis, Septic arthritis or IV drug abusers Previous history of acute attack in the joint with spontaneous resolution Gout, any inflammatory arthritis History of sustained bleeding (coagulopathy) or use of anticoagulants Hemarthrosis Positive family history Gout, IBD-induced spondyloarthropathy, psoriasis, ankylosing spondylitis, osteoarthritis Prolonged use of corticosteroid in the recent past Infection, avascular necrosis Urethritis (chlamydiae), conjunctivitis, skin or penile rash, diarrhea Reactive arthritis (ReA) (campylobacter, salmonella, shigella) Arthritis precipitated after binge alcohol intake or consumption of Gout diuretics Low back pain, uveitis (red eye), heel pain, or Achilles tendonitis Ankylosing spondylitis Hilar adenopathy, erythema nodosum (Lofgren syndrome) Sarcoidosis Bedside clinics: zz Oral ulcers zz Behçet’s disease, SLE, ReA zz Pyrexia zz Infection, crystals, immunoinflammatory zz Lymphadenopathy zz Tuberculosis, malignancy zz Tophi over olecranon process, or helix zz Gout zz Erythematous rash in face zz SLE (butterfly-like), lupus pernio (sarcoidosis) zz Bronzing (darkening) of skin zz Pseudogout (hemochromatosis) zz Pyoderma gangrenosum zz IBD, RA zz Erythema nodosum zz IBD, SLE, sarcoidosis, tuberculosis zz Psoriatic skin patches or pitting nails zz Psoriatic arthritis zz Circinate balanitis or keratoderma blenorrhagicum zz ReA

TABLE 4 Acute monoarthritis presenting as ‘red-hot joint’4 Pitfalls and Reality in Monoarthritis

Infectious Bacterial (Staphylococci, Streptococci, (Table 5) Gonococci, gram-negative organisms), viral Management Crystal-induced Gout, pseudogout (i.e., from Management of acute monoarthritis depends on the hemochromatosis, acromegaly, actual diagnosis though the general principles of hypoparathyroidism) management include rest to the joint, application of ice, Acute exacerbation of: RA, ReA, PsA, palindromic rheumatism and physiotherapy to help maintain range of motion in joints and minimize subsequent muscle atrophy. Specific therapy includes antibacterial agents for septic arthritis, serum uric acid, and rheumatoid factor. Radiology is not non-steroidal anti-inflammatory drugs (NSAIDs) and/ much helpful except in sacroiliitis, osteoarthritis, and or intra-articular corticosteroid injections for non- chondrocalcinosis (e.g., pseudogout). MRI may be helpful infectious inflammatory monoarthritis; arthroscopy is in deep-seated arthritis. performed for internal derangement. Presence of infection

MU-208.indd 1335 29-01-2021 15:25:18 1336 SECTION 16 Rheumatology and CTD

TABLE 5 Pitfalls versus reality in diagnosing monoarthritis5

Pitfalls Reality A normal serum uric acid level excludes gout Serum uric acid may be normal or low up to 30% cases of gout as stress-induced liberation of ACTH and TNF-α may act uricosuric. Moreover, there may be unrelated asymptomatic hyperuricemia associated with other monoarticular arthritis Presence of fever distinguishes infective from non-infective arthritis Presence of fever is not a reliable indicator of septic arthritis, and moreover acute attack of gout or pseudogout may be associated with pyrexia. Similarly, absence of leukocytosis, raised ESR, raised CRP, or absence of organisms does not exclude septic arthritis Presence of crystals (MSU or CPPD) in the joint fluid rules out Crystal may be present in septic arthritis infection The problem is always in the ‘joint’ as the patient complains of joint Many a time, soft tissue rheumatism due to adjacent soft tissue pain inflammation (such as olecranon bursitis of the elbow) may be the source of pain Diseases manifested as polyarthritis cannot have monoarthritis-like Monoarticular flare of rheumatoid arthritis or reactive arthritis is not presentation uncommon A negative Gram staining and culture of synovial fluid virtually Results of culture may be negative in early infection, and thus culture excludes infection of blood/urine should be performed repeatedly in strong clinical suspicion of infection In synovial fluid analysis, presence of WBC >2,000/mm3 clinches the Synovial fluid WBC >2,000/mm3 is very often found in RA, SpA, SLE, diagnosis of septic arthritis or gout

should always be ruled out before giving intra-articular indicated, it should be treated as septic arthritis. corticosteroid injection. Acute gout should be treated with Other D/D are acute gout, trauma, and acute onset of colchicine, NSAIDs, or prednisolone. Joint aspiration is inflammatory polyarthritis. necessary in hemarthrosis. Osteoarthritis patients are „„ The most significant point of clinical examination advised to save their cartilage by practical demonstration, is to differentiate true synovitis (i.e., arthritis) from and treated with intra-articular corticosteroid and/or periarticular disease (e.g., cellulitis, bursitis, etc.). hyaluron injection. Pain in reactive arthritis is relieved by „„ Septic arthritis can destroy a joint very rapidly, if not NSAIDs and ultimately the patients are advised to take treated promptly. Septic arthritis is often superimposed disease-modifying anti-rheumatic drugs (DMARDs). on gout or pseudogout. Gonococcal arthritis is If the clinical suspicion of septic arthritis is very strong, commonly a disease of sexually active young women. empiric antibiotic therapy should be started, pending „„ RA, ReA, IBD-associated arthritis, SLE, PsA, Behçet’s the reports of synovial fluid analysis. Modifications of disease can begin as acute monoarthritis, while antibiotics and its dosage may be done as soon as Gram systemic diseases like sarcoidosis, sickle cell anemia, staining and culture reports of synovial fluid are available. or hemophilia may be complicated by monoarthritis. Septic arthritis should be treated in a hospital under Tuberculosis and other indolent infections should be the supervision of an orthopedic surgeon. Many a time, considered in chronic monoarthritis, and synovial surgical drainage of a septic arthritis is required. biopsy may be needed to pin-point the diagnosis. „„ The synovial fluid should be aspirated and sent for Practical Recommendations for Acute Gram staining and cultures (apart from total analysis) 1,6 in acute and chronic monoarthritis. Synovial fluid Monoarthritis analysis is the most important investigation. „„ Acute monoarthritis is a medical emergency. With „„ Absence of leukocytosis/high ESR/high CRP, negative a short history of red-hot swollen joint, one should Gram stain, or negative synovial fluid cultures does not always suspect infection and unless otherwise exclude infection.

MU-208.indd 1336 29-01-2021 15:25:18 Monoarthritis—A Clinical Dilemma to Internists CHAPTER 208 1337

„„ In gout, synovial fluid samples must be sent for References polarized microcopy for demonstration of intracellular . 1 Thabah MM, Chaturvedi V. An approach to monoarthritis. J MSU crystals as serum uric acid may be normal Mahatma Gandhi Inst Med Sci. 2014;19(1):12-8. in acute attack of gout; in its absence, ordinary . 2 Baker DG, Schumacher HR. Acute monoarthritis. NEJM. microscopy often gives a clue for crystals. 1993;329(14):1013-20. „„ Plain X-ray of the affected joint is usually of no benefit. . 3 Ralston SH, McInnes IB. Presenting problems in musculoskeletal disease. In: Walker BR, Colledge NR, Ralston SH, Penman ID (Eds). „„ In septic arthritis, start relevant antibiotics as early Davidson’s Principles and Practice of Medicine, 22nd edition. as possible pending culture reports. Usual pathogens London: Churchill Livingstone Elsevier; 2014. pp. 1069-70. are Staphylococcus aureus or streptococci but Gram- 4. Horowitz DL, Katzap E, Horowitz S, et al. Approach to septic arthritis. negative organisms are commoner in the elderly and Am Fam Phys. 2011;84(6):653-60. immunocompromised patients. Conventionally, IV . 5 Ma L, Cranney A, Holroyd-Leduc JM, et al. Acute monoarthritis: antibiotics are given for 2 weeks, followed by oral what is the cause of my patient’s painful swollen joint? Canadian Med Assoc J. 2009;180(1):59-65. antibiotics for 4 weeks or more till local/systemic 6. Goldenberg DL. Septic arthritis. Lancet. 1998;351(9097):197-202. manifestations resolve and acute phase reactants (e.g., CRP) return to normal. „„ Septic arthritis should be treated by orthopedic surgeon, crystal arthropathy, and inflammatory arthritis by rheumatologist, and osteoarthritis by orthopedic surgeon and physiatrist jointly.

Conclusion Acute monoarthritis is a rheumatologic emergency and demands prompt diagnosis. So far as diagnosis and treatment of chronic monoarthritis are concerned, it needs patience, sound clinical background, and experience. Prompt diagnosis of joint infection is crucial as it rapidly results in joint destruction. Before putting the needle within a joint to inject corticosteroid, it is the duty of orthopedic surgeon or rheumatologist to exclude infective arthritis. The diagnostic and therapeutic dilemma in monoarticular arthropathy can be solved easily if the attending doctor examines the patient meticulously, and analyze the clinical findings and investigation reports logically.

MU-208.indd 1337 29-01-2021 15:25:18 CHAPTER

Oral Targeted Treatments in 209 RA—Update 2021

Ramakrishna Rao Uppuluri, Sripurna Deepti Challa

Abstract The current concept in the management of rheumatoid arthritis (RA) and other immune-inflammatory arthritis is “treat to target”, the target being low disease activity or remission. The standard of care in RA involves pharmacotherapy initiating conventional synthetic disease modifying anti-rheumatoid drugs. However, some patients do not respond to the conventional therapy. Advanced target therapy for RA involves biologic agents or oral small molecules. JAK inhibitors, a form of oral targeted treatment, are convenient, orally administered which do not produce drug antibodies. Robust clinical trials demonstrated their efficacy and safety.

Introduction Advances in the Treatment of RA Among the inflammatory polyarthritis, rheumatoid In the treatment of RA, csDMARDs occupy a central arthritis (RA) is the most common. Over the past few role (Flowchart 1). MTX is still a baseline therapy un­ decades, significant advances were made in understanding less contraindicated. Most of the rheumatologists use the pathogenesis of RA. The role of several important combination therapy with csDMARDs.1 proinflammatory cytokines, such as tumor necrosis factors However, significant number of the patients of RA do (TNF), interleukins (e.g., IL-6), and cell-associated targets continue to progress with erosive arthritis. Biologic era in (e.g., CD20) have been validated by the use of targeted the past few years had seen remarkable advancement in biologic therapies in last two decades. Standard of care in the therapy of RA. In view of persistent unmet needs in RA involves initiation of the treatment with conventional the management of RA, oral targeted therapy inhibiting synthetic disease modifying anti-rheumatoid drugs intracellular signaling pathways is developed in the last (csDMARDs) such as methotrexate (MTX). Biologic decade (Fig. 1).2 therapies (bDMARDs) have led to further reduction of the signs and symptoms of RA resulting in low disease activity Oral Targeted Therapy: (LDA) or remission of the disease. However, they have limitations—they have to be given parenterally and stored Janus Kinase Inhibitors at lower temperatures. They can induce immunogenicity Intracellular signaling pathways involved in signal developing tolerance. Small molecules with low molecular transduction from the cell surface to the nucleus after mass that inhibit intracellular inflammatory signaling ligand receptor binding have been identified. Small pathways are developed during the last decade. They are molecular therapies target these intracellular pathways. an important alternative to biologics for RA. These are Protein kinases that phosphorylate intracellular proteins called oral targeting treatments of RA. are major players in signal transduction. Tyrosine kinases,

MU-209.indd 1338 29-01-2021 15:25:04 Oral Targeted Treatments in RA—Update 2021 CHAPTER 209 1339

Flowchart 1: Classification of DMARDs

Fig. 1: Timeline in RA therapy (FDA approvals) Arrival of oral targeted treatment—JAKinibs

Janus kinases (JAKs), and Serine kinases are some of the nucleus, and activate new gene transcription generating protein kinases (Flowchart 2). further cytokines (Figs. 2C and D).3 Receptor polymerization and activation of associated JAK inhibitors (Jakinibs) have been successfully JAKs occur once the cytokine binds to its cell surface developed as oral targeted therapy in RA. receptor. JAKs, named after the two-faced Roman God Autophosphorylation and further activation of JAKs is Janus, consist of four types—JAK1, JAK2, JAK3, and TYK2. inhibited by Jakinibs, for example, Tofacitinib. JAKs cannot Phosphorylation of the receptors activated by JAKs dock phosphorylate the receptors and cannot dock the STATs. the STATs (Signal Transduction Activator Transcription) Phosphorylation of STATs, dimerization, and translocation (Figs. 2A and B). They dimerize, translocate to the are inhibited. Hence, gene transcription and further

MU-209.indd 1339 29-01-2021 15:25:05 1340 SECTION 16 Rheumatology and CTD

production of cytokines do not take place (Fig. 3). There preferentially recruit different STATs by virtue of selective are seven STATs: STAT1, STAT2, STAT3, STAT4, STAT5A, binding to cytokine receptors.4 The JAK/STAT pathways STAT5B, and STAT6. Different cytokines have the ability to exert their function through type I and type II receptors. Type I receptors are used by several interleukins (ILs), colony-stimulating factors, and hormones, while type II Flowchart 2: Small molecules—intracellular targets receptors are used by interferons (IFNs) and IL-10 related cytokines (Fig. 4).5 Tofacitinib, one of the early Jakinibs, was approved in the USA in 2012 for the treatment of moderately severe RA not responding to conventional therapy and was approved in India by 2016. Baricitinib, another Jakinib, is also approved in India for the treatment of RA more than a year ago. Upadacitinib and Filgotinib are other Jakinibs yet to enter Indian market. All these molecules have undergone robust clinical trials for efficacy in RA6 (Tables 1 and 2). Randomized controlled trials (RCT) and long- term extension (LTE) studies have shown that Jakinibs are as efficacious as biologics. Safety profiles of these Jakinibs have also been carefully monitored long term.7 Tofacitinib in Indian patients with RA had confirmed its efficacy and safety by a post hoc analysis in Phase 3 and LTE studies over 7 years.8 The Place of Jakinibs in Contemporary RA Management Tofacitinib and baricitinib are currently available Jakinibs for the treatment of patients with moderately severe RA

A B

C D

Figs. 2A to D: JAK signaling pathways

MU-209.indd 1340 29-01-2021 15:25:08 Oral Targeted Treatments in RA—Update 2021 CHAPTER 209 1341

not responding to conventional DMARDs. Tofacitinib targets mainly JAK1, JAK3 and Baricitinib JAK1, JAK2. Tofacitinib is also approved in other disorders such as psoriatic arthritis (PsA) and ulcerative colitis (UC). Many more Jakinibs are in the process of randomized clinical trials9 (Table 3).

Drug Target Indications American College of Rheumatology (ACR) guidelines and European League against Rheumatism (EULAR) recommendations for the management of RA advise use of MTX to begin with.10,11 However, only a third of patients with early RA benefit from MTX monotherapy in controlling disease activity, improving patient reported outcome measures (PROMs) and slowing radiographic progression.12 The ACR guidelines recommend combination of csDMARDs or Fig. 3: Mode of action of JAK inhibitor (see text for the explanation)

Fig. 4: Cytokines, JAK combinations and functions

MU-209.indd 1341 29-01-2021 15:25:09 1342 SECTION 16 Rheumatology and CTD

TABLE 1 Tofacitinib in RA—phase 3 studies: overview

DMARD-IR MTX-IR TNFi-IR MTX naïve Study(N) ORAL solo ORAL Sync ORAL Standard ORAL Scan Oral Step ORAL Start (N=610) (N=792) (N=717) (N=797) (N=399) (N=952) Duration 6 12 12 24 6 24 months Background None Nonbiologic MTX MTX MTX None treatment DMARDs Feature Monotherapy Background Active control (ADA) Radiographic TNFi failure Radiographic cDMARDs outcomes data (X-ray) monotherapy Primary ACR20 ACR20 ACR20 ACR20 ACR20 ACR70 endpoints HAQ-DI HAQ-DI DAS28-4 HAQ-DI HAQ-DI DAS28-4 (ESR) HAQ-DI DAS28-4 (ESR) mTSS DAS28-4 (ESR) DAS28-4 (ESR) (ESR) ACR, American College of Rheumatology; ADA, adalimumab; BARI, baricitinib; cDMARDs, conventional disease modifying antirheumatic drugs; DAS, disease activity score; HAQ-DI, health assessment questionnaire-disability index; IR, inadequate responders; mTSS, modified total sharp score; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.

TABLE 2 Baricitinib in RA—phase 3 clinical trials overview

DMARD naïve cDMARD-IR Biologic IR RA BEGIN MTX-naïve RA BEAM MTX-IR RA BUILD cDMARD-IR RA BEACON TNFI-IR MTX PBO PBO PBO BARI 4 mg mono BARI 4 mg + MTX BARI 2 mg BARI 2 mg BARI 4 mg + MTX ADA 40 mg + MTX BARI 4 mg BARI 4 mg 52 weeks 52 weeks 24 weeks 24 weeks RA BEYOND (long-term extension) ADA, adalimumab; BARI, baricitinib; cDMARDs, conventional disease modifying antirheumatic drugs; IR, inadequate responders; MTX, methotrexate; PBO, placebo; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.

TABLE 3 Some JAKINIBS—their targets and indications

Drug Target Indication Tofacitinib (Xeljanz) JAK1, JAK3, JAK2 RA (approved in India also), PsA, UC Baricitinib (Olumiant) JAK1, JAK2 RA (approved in India also) Peficitinib (Smyraf) JAK1,2,3, TYK2 RA (approved in Japan) Upadacitinib (Rinvoq) JAK1 RA (approved in USA) Filgotinib JAK1 RA (completing clinical trials) Decernotinib JAK3 RA (continuing clinical trials) BMS-986165 TYK2 PsA (started clinical trials)

MU-209.indd 1342 29-01-2021 15:25:09 Oral Targeted Treatments in RA—Update 2021 CHAPTER 209 1343

Fig. 5: RA treatment—EULAR recommendations 2019 update

addition of a bDMARD or a Jakinib, when the patients fail activity, early joint damage and/or failure of two or more to achieve a satisfactory response to MTX monotherapy csDMARDs (Fig. 5). and a short period of glucocorticoids. Jakinibs with Real world evidence for safety and efficacy of Jakinibs or without MTX are also considered in bDMARD is also necessary to bridge the gap between RCTs and inadequate responders. EULAR recommendations also rheumatology clinics.13 Usually there is little difference advise similar management for RA, especially with poor in the screening and monitoring of infections between prognostic factors such as high titers of RF/ACPA (anti Jakinibs and biologics. Increased risk of Herpes zoster cyclic citrullinated protein antibodies), high disease may be common to all Jakinibs. In real world practice,

MU-209.indd 1343 29-01-2021 15:25:10 1344 SECTION 16 Rheumatology and CTD

biologics except Herpes zoster.19 The risk of reactivation Some of the ongoing clinical trials with JAKINIBS TABLE 4 other than RA of varicella zoster virus is increased by the use of Jakinibs with the combination of steroids and MTX. Before starting zz Juvenile arthritis zz Psoriasis therapy with Jakinibs, vaccination against Herpes zoster is zz Ankylosing spondylitis zz Alopecia areata considered. Treatment with Jakinibs can cause anemia and zz Psoriatic Arthritis zz Atopic dermatitis zz Crohn’s disease zz Vitiligo decreased cell counts including lymphocytes, neutrophils, 20 zz Ulcerative colitis zz Scleroderma and platelets. There is no particular association of these zz Uveitis zz Lupus changes with serious infections or malignancy. zz Sjogren’s syndrome zz Vasculitis Tuberculosis accumulation of cases to evaluate risks of relatively RA itself can increase the susceptibility to tuberculosis rare serious adverse events (SAEs) is needed. Some of (TB). Biologics especially the TNF inhibitors increase the SAEs are thromboembolic events, gastrointestinal the risk of TB, mostly in an endemic area. The incidence (GI) perforation, and interstitial lung disease. is less with Jakinibs. Among 5,671 subjects enrolled in Pharmacovigilance activity is required to establish the Phase 2 and 3 and LTE studies of Tofacitinib, 26 cases of efficacy and safety of Jakinibs in patients with RA and TB were reported. The median time between the start of other rheumatic diseases (Table 4). Tofacitinib and diagnosis of TB was 64 weeks (15–161). Extrapulmonary infection occurred in fifteen (58%) Advantages of Jakinibs cases. Most cases (20/26, 77%) were reported in those taking Tofacitinib 10 mg twice a day. However, globally Jakinibs are orally administered small molecules unlike Tofacitinib dosage is only 5 mg BID in RA. TB rate with biologics, which are large proteins and given only by 21 Jakinibs was also associated with endemicity. subcutaneous or intravenous.14 Jakinibs act fast showing their benefits within 1–2 weeks. Small molecules can be Thromboembolic Events synthesized easily, carried easily, and do not require cold Possibility of increased risk of thromboembolic events is chain. They do not have immunogenicity seen in some noted with the use of Baricitinib. RA itself has a tendency biologics; hence do not generate drug antibodies. Since to develop the risk of deep venous thrombosis and their half-life is short for a few hours, they can be stopped pulmonary embolism. Relating this complication to the in situation where infection is suspected with a rapid action of a specific or a group of cytokines is difficult. JAK2 reversal of drug-related side effects. Blockade of a wide inhibition disturbs thrombopoietin signaling and platelet spectrum of cytokines may cover many inflammatory homeostasis, but its relation to thrombosis is ill-defined.22 pathways. Tofacitinib and Baricitinib with background MTX proved to be non inferior and superior respectively Malignancy over standard of care biologic Adalimumab in active RA.15 PROMs, such as pain, function and fatigue are improved Patients with RA have an increased incidence of malig­ 16,17 nancy including lymphoma. The rate of cancer in patients very well with Jakinibs. 23 Jakinibs are proved to be beneficial and convenient on Jakinibs is similar to those on biologics (Table 5). even as monotherapy in RA. Tofacitinib in ORAL-Start Other Problems study, Baricitinib in RA-Begin study, and Upadacitinib in SELECT-Early study have shown superiority over MTX on Jakinibs are associated with an increase in total clinical, functional, and radiographic measures.18 cholesterol, low-density lipoprotein (LDL), and high- density lipoprotein (HDL) particles. Jakinibs may limit Side Effects of Jakinibs vascular damage by decreasing inflammation in spite of increased cholesterol.24 Minimal increases in creatine Infections phosphokinase levels are observed without overt muscle Usage of Jakinibs may increase serious and opportunistic disease. The use of Jakinibs may be associated with infections. However, the rate of infections is not more than increased liver enzymes and GI perforation. Jakinibs are

MU-209.indd 1344 29-01-2021 15:25:10 Oral Targeted Treatments in RA—Update 2021 CHAPTER 209 1345

TABLE 5 Incidence rates of adverse events of special interest of JAKINIBS in RA

Adverse events Tofacitinib Baricitinib Serious infection 2.7 (2.5, 3.0) 2.9 (2.5, 3.4) Herpes zoster 3.9 (3.6, 4.2) 3.2 (2.8, 3.7) Tuberculosis 0.2 (0.1, 0.3) 0.15 (0.07, 0.27) Malignancy excluding NMSC 0.9 (0.8, 1.0) 0.8 (0.6, 1.0) NMSC 0.6 (0.5, 0.7) 0.4 (0.2, 0.5) Lymphoma 0.1 (0.1, 0.2) 0.09 (0.03, 0.19) MACE 0.58 (0.39, 0.88) 0.5 (0.4, 0.7) DVT/PE DVT: 0 in PBO-controlled cohort and 0.1 (0, 0.3) in dose-comparison cohort DVT/PE: 0.5 (0.3, 0.7) PE: 0 in PBO-controlled cohort and 0.1 (0, 0.4) for 5 mg bid GI perforation 0.11 (0.07, 0.17)a 0.05 (0.01, 0.13) Incidence rates (95% CIs) in RA patients treated with each JAK inhibitor were shown. DVT, deep vein thrombosis; GI, gastrointestinal; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer; PBO, placebo; PE, pulmonary embolism.

contraindicated at the time of pregnancy. Women of child- . 4 Gadina M, Le M, Schwartz D, et al. Janus kinases to Jakinibs: from bearing age should use effective contraception while on basic insights to clinical practice. Rheumatology. 2019;58(1):4-16. treatment. During breastfeeding, Jakinibs should not be . 5 O’Shea JJ, Kontzias A, Yamaoka K, et al. Janus kinase inhibitors in used. autoimmune diseases. Ann Rheum Dis. 2013;72(2):111-5. 6. Taylor PC. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology. 2019;58(1):17-26. Conclusion . 7 Wallenhaupt J, Lee EB, Curtis JF, et al. Safety and efficacy of zz JAK inhibitors are the latest addition of the treatment of RA tofacitinib for up to 9.5 years in the treatment of rheumatoid in the last decade. arthritis; final results of a global, open-label, long-term extension zz They act by blocking intracellular JAK/STAT signaling study. Arthritis Res Ther. 2019;21(1):89. pathways inhibiting the production of inflammatory . 8 Chopra A, Shobha V, Chandrashekara S, et al. Tofacitinib in the cytokines. treatment of Indian patients with rheumatoid arthritis: a post hoc zz They are rapidly acting, oral targeting anti-rheumatoid analysis of efficacy and safety in phase 3 and long-term extension drugs with convenience. studies over 7 years. Int J Rheum Dis. 2020;23(7):882-97. zz They showed sustained efficacy and established safety by . 9 Westhovens R. Clinical efficacy of new JAK inhibitors under robust clinical drug trials and real world experience. development. Just more of the same? Rheumatology. 2019;58(1): zz Recommended as a second line therapy for csDMARDs 27-33. inadequate responders or Biologic inadequate responders 10. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 ACR guideline for the by several guidelines. treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68(1):1-25. 11. Smolen JS, Landewé RBM, Bijlsma WJF, et al. EULAR recommendations for the management of rheumatoid arthritis References with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-99. . 1 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a 12. van Vollenhoven RF, Ernestam S, Geborek P, et al. Addition randomized trial. Ann Intern Med. 2007;146(6):406-15. of infliximab compared with addition of sulfasalazine and . 2 O’Shea J, Laurence A, McInnes I, et al. Back to the future: oral hydroxychloroquine to methotrexate in patients with early targeted therapy for RA and other autoimmune diseases. Nat Rev rheumatoid arthritis (Swefot trial): 1-year results of a randomized Rheumatol. 2013;9(3):173-82. trial. Lancet. 2009;374(9688):459-66. 3. Villarino AV, Kanno Y, O’Shea JJ, et al. Mechanisms and consequences 13. Rao URK, Rao VK. Clinical experience of tofacitinib in rheumatoid of JAK-STAT signaling in the immune system. Nat Immunol. arthritis: real-world data from 2 centres in South India. Int Rheum 2017;18(4):374-84. Dis. 2018;204-5.

MU-209.indd 1345 29-01-2021 15:25:10 1346 SECTION 16 Rheumatology and CTD

14. Alten R, Kruger K, Rellecke J, et al. Examining patient preferences 19. Strand V, Ahadieh S, French J, et al. Systematic review and meta- in the treatment of rheumatoid arthritis using a discrete-choice analysis of serious infections with tofacitinib and biologic disease- approach. Patient Prefer Adherence. 2016;10:2217-28. modifying anti-rheumatic drug treatment in rheumatoid arthritis 15. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus clinical trials. Arthritis Res Ther. 2015;17:362. placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 20. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of 2017;376(7):652-62. baricitinib for the treatment of rheumatoid arthritis up to six 16. Strand V, Mysler E, Moots RJ, et al. Patient-reported outcomes for years: an updated integrated safety analysis [abstract]. Arthritis tofacitinib with and without methotrexate, or adalimumab with Rheumatol. 2018;70(10). methotrexate, in rheumatoid arthritis: a phase IIIB/IV trial. RMD 21. Harigai M. Growing evidence of the safety of JAK inhibitors in Open. 2019;5(2):001040. patients with rheumatoid arthritis. Rheumatology. 2019;58(1):34-42. 17. Uppuluri RR, Younis M, Rani A, et al. Real-world experience of 22. Verden A, Dimbil M, Kyle R, et al. Analysis of spontaneous postmarket efficacy and patient reported outcome measures (PROMs) of case reports submitted to the FDA regarding thromboembolic tofacitinib in patients with active rheumatoid arthritis. Indian J adverse events and JAK inhibitors. Drug Saf. 2018;41(4):357-61. Rheum. 2019;2(133). 23. Mariette X, Chen C, Biswas P, et al. Lymphoma in the tofacitinib 18. van Vollenhoven R, Takeuchi T, Pangan AL, et al. Efficacy and rheumatoid arthritis clinical development program. Arthritis Care safety of upadacitinib monotherapy in methotrexate-naive Res (Hoboken). 2018;70(5):685-94. patients with moderately to severely active rheumatoid 24. Kume K, Amano K, Yamada S, et al. Tofacitinib improves arthritis (SELECT-EARLY): a randomized, double-blind, atherosclerosis despite up-regulating serum cholesterol in patients active-comparator, multicenter, multi-country trial. Arthritis with active rheumatoid arthritis: a cohort study. Rheumatol Int. Rheum. 2020. 2017;37(12):2079-85.

MU-209.indd 1346 29-01-2021 15:25:10 CHAPTER

Biosimilars: 210 Bane or Boon for India

Durga Prasanna Misra, Pallavi Patro, Vikas Agarwal

Abstract Biosimilars are structural analogues of innovator biological drugs which have undergone rigorous development and testing. In this chapter, we overview definitions of biosimilars, biomimics, and biocopies; review regulatory processes for biosimilar approval; and discuss the concepts of extrapolation, switch, substitution, re-switch, and nocebo effect as assess perspectives for biosimilar use (including cost) from an Indian perspective.

Introduction are amenable to manufacture locally as well as not covered by any existing patents. Therefore, biosimilars are cheaper Better understanding of pathophysiological process and more accessible. The recent past has seen a flooding of driving disease has given rise to targeted therapies the local market for such biosimilar drugs. In this chapter, for the treatment of these diseases. Biologic drugs are we discuss the impact of biosimilar agents (benefits as well drugs administered parenterally, which target specific as costs) and their comparability in terms of effectiveness molecular pathways resulting in disease phenotypes. and adverse effects, as well as issues such as nocebo Biologic drugs are now used in many medical specialties effect, which potentially limit their use in patients.4 We such as Rheumatology, Hematology, Oncology, and also discuss certain peculiar adverse effects occasionally Nephrology.1-3 described with biosimilars. The classical example of a biologic drug that has revolutionized patient management in drugs targeting the proinflammatory cytokine tumor necrosis factor alpha Biosimilars and Biomimics/Biocopies (TNF-α) in disease settings like rheumatoid arthritis (RA) Biologic drug synthesis is complex, in that it relies on and ankylosing spondylitis (AS). Such anti-TNF therapies recombinant deoxyribonucleic acid (DNA) technology have become frontline agents for the management of these for synthesis of these molecules. Biosimilars are similarly lifelong inflammatory diseases, and markedly improved synthesized using recombinant DNA technology,5 so disease control in those refractory to conventional also are biomimics or biocopies with similar molecular disease-modifying antirheumatic drugs. However, despite structure (primary, secondary, and tertiary). However, their use being described in RA and AS since the late biosimilars differ from biomimics or biocopies in that 1990s, anti-TNF agents remained out of reach for a they also have been demonstrated to have equivalent majority of the Indian populace until recently, in no small effect on disease states in preclinical and clinical trials, part due to prohibitive costs.2 A major reason for increased as well as demonstrate similar pharmacokinetic and accessibility has been the advent of biosimilar drugs, pharmacodynamic properties (including immunogenicity) which are copies of the innovator biologic drug, however, to the innovator biologic drugs.6

MU-210.indd 1347 29-01-2021 15:24:46 1348 SECTION 16 Rheumatology and CTD

Regulatory Processes for Approval of biosimilar, which was introduced in South America as a cheaper alternative to innovator erythropoietin analogue. Biosimilar Drugs This drug was primarily intended for use in patients The two major agencies regulating drug approval in with chronic kidney disease with anemia (which often the world, the European Medicines Agency (EMA) and results due to erythropoietin deficiency). Unusually, the United States Food and Drug Administration (US some patients treated with erythropoietin biosimilar FDA) have laid down guidelines for the approval of developed pure red cell aplasia, resulting in refractory biosimilar drugs. Broadly, the similar protein structure transfusion-dependent anemia.10 This was a consequence of the innovator biologic drug and the biosimilar should of antibodies that neutralized the effect of erythropoietin be demonstrable, followed by studies that demonstrate due to differences in immunogenicity of the biosimilar equivalence in pharmacokinetic and pharmacodynamic molecule.10 Such issues were later rectified in future properties with innovators. Thereafter, efficacy and safety erythropoietin biosimilars by modifying the protein of biosimilar drugs with innovator biologic drugs should structure to ameliorate such abnormal immunogenicity.7 be demonstrated before consideration for approval. This is a case in point, which reiterates the need to Ideally, equivalence with innovator (i.e. neither a clinically seek long-term safety of biosimilars that are eventually significant detriment nor benefit when compared with approved and marketed by means of continual post- innovator biologic) should be demonstrated rather than marketing surveillance.11 non-inferiority (i.e. simply the lack of a clinically significant detriment). Furthermore, since these are foreign proteins, Extrapolation the lack of significant difference in immunogenicity when Another term often used in the context of biosimilars is compared with innovator biologic drugs should also be extrapolation. Many a times, the same biologic drug is demonstrable. Mere identity in protein structure without used for a number of disease states. For example, anti- demonstrating the other steps mentioned simply results TNF agents are used in RA, AS, psoriatic arthritis (PsA), in a biomimic. Such biomimics have been noted to have inflammatory bowel diseases (IBD), and sarcoidosis. a greater propensity to develop adverse effects than Should a biosimilar be shown to be equivalently efficacious innovators, and are often in vogue in regions of the world to the innovator in RA, this is often extrapolated to assume with poor regulatory policies.7-9 The approval processes its effectiveness to a similar degree in the other disease for biosimilars in India are broadly in line with the EMA states it is indicated for, such as AS, PsA, and IBD. This and US FDA standards. This requires approvals from the is a common practice with biosimilars; however, due Central Drugs Standards Control Organization (CDSCO). caution and careful post-marketing surveillance should accompany any such extrapolation of indication for the Are Biosimilars the Same as Generic Drugs? 12 use of biosimilars. A common source of confusion is generic drugs and biosimilars. It is important to understand that generic Switch, Substitution, and Re-switch drugs are mere chemicals with identical structure to the Switch refers to the decision of the treating clinician to original molecules. The generation of biologic drugs has change a biologic drug from innovator to biosimilar, or vice the added complexity that they require biologic systems versa. If such a decision is taken by somebody who is not the for the generation of their recombinant protein structure; treating physician, say, a regulatory authority or the hospital hence, they are thematically more complex to generate administration (due to costs or other concerns), this is and attain equivalence to innovators when compared with instead referred to as a substitution (also known as a non- chemical generic drugs.7 medical switch). After an initial switch, it is possible to re- switch back and forth between the two products, depending The Need for Post-marketing Surveillance 1 on feasibility issues such as availability, ability to afford, etc. for Long-term Safety of Biosimilars Switching offers an opportunity to provide head-to- An often-quoted tale of caution regarding biosimilar use head comparisons between innovators and biosimilars. has been the example of recombinant erythropoietin Analysis of more than 300 patients with IBD from Sweden

MU-210.indd 1348 29-01-2021 15:24:46 Biosimilars: Bane or Boon for India CHAPTER 210 1349

switched from innovator infliximab to biosimilar infliximab In the setting of rheumatic diseases, biosimilar drugs have CT-P13 revealed similar disease activity state at 12 months not shown significant differences compared to innovator of observation.13 In another study from the Netherlands, drugs in blinded randomized controlled trials. However, 625 patients switched to biosimilar etanercept were open-label clinical trials and real-life registry data have compared with a historical cohort of 600 patients treated often demonstrated lower retention rates (and higher with innovator etanercept at the same region. Indications rates of switch back to innovator drug) with biosimilars. for etanercept use in these patients were inflammatory This might be due to the perceived ineffectiveness of arthritides (RA, AS, and PsA). At 6 months, retention rates these drugs by the patients, which is supported by the of the biosimilar (in the switched cohort) or innovator (in fact that many such switches are based on subjective the historical cohort) were nearly 90%, although patients (rather than objective) measures of ineffectiveness. Such switched to etanercept biosimilar had a slightly higher a nocebo effect has the potential to limit the cost-saving risk of discontinuation.14 A Scandinavian biologic registry effect of biosimilars at an aggregated level by limiting spanning five countries compared retention rates for their utilization.4 However, the authors perceive that infliximab (innovator 320, biosimilar 999 patients) and nocebo effect might be a particular problem in societies etanercept (innovator 493, biosimilar 522) in patients with where health care is nationalized. In countries like India, spondyloarthritis. At 1-year follow-up, 66% treated with where a majority of the time patients pay out-of-pocket to etanercept biosimilar continued the same compared with afford biologic drugs, the lower cost of biosimilar agents 73% treated with etanercept innovator; corresponding is likely to reduce the likelihood of nocebo effect (since figures for infliximab at 2-years were 44% for biosimilar affordability now becomes the major concern rather than and 46% for innovator, suggesting similar rates of retention perceived effectiveness). irrespective of biosimilar or innovator molecule.15 A comparison of more than 1,600 etanercept biosimilar switchers with more than 400 non-switchers (continuing Perspectives from India on innovator etanercept) from Denmark for RA, AS, and Regarding Biosimilars PsA revealed numerically higher retention rates at 1 Overall published literature regarding the effectiveness of year for switchers than non-switchers (although of little biosimilars from India is scarce. A significant chunk of the 16 difference in magnitude and not significant statistically). available literature relates to a biosimilar of adalimumab A long-term follow-up of patients for 52 weeks switched to (ZRC-3197). Regulatory approval was obtained after biosimilar infliximab compared with innovator infliximab proving efficacy of this adalimumab biosimilar in patients in a randomized trial (NOR-SWITCH trial) for a variety of with RA when compared with innovator adalimumab.2 multisystem inflammatory diseases revealed similar rates Thereafter, real life data regarding ZRC 3197 use in 51 17 of efficacy and safety. An expected benefit of switching is patients with spondyloarthritis and 39 patients with RA lesser health-care costs; however, a recent analysis of 1620 was published. At an observation period of 1 year after recipients of etanercept biosimilar from Denmark did not treatment, more than 90% patients with spondyloarthritis reveal a significant cost-saving in the year following the had attained clinical remission. Nearly 60% of the cohort 18 switch compared to the year preceding it. Hence, the with RA also attained control of disease activity.19 Post- cost-effectiveness of switching biosimilars needs further marketing surveillance under the Adalimumab Biosimilar evaluation. Patient Registry (ASPIRE) further recently reported data in relation to RA and spondyloarthritis. In 73 patients with Nocebo Effect RA, significant reductions in disease activity were noted by A perceived lesser degree of response to a drug owing to 24 weeks; nearly one-half patients attained good control psychological or contextual factors might be described of disease activity.20 For 100 patients with AS treated with as a nocebo effect. This is thematically the antithesis of a adalimumab biosimilar in this same ASPIRE registry, placebo effect (i.e. perceived positive effect of a placebo, adequate control of disease activity with attainment when no active drug is being administered). Biosimilar of Bath Ankylosing Spondylitis Disease Activity Score drug use in real life might be affected by the nocebo effect. (BASDAI) below 4 at 24 weeks of observation was possible

MU-210.indd 1349 29-01-2021 15:24:47 1350 SECTION 16 Rheumatology and CTD

BOX 1 Recommendations of the EULAR, GRS, and PANLAR regarding the use of biosimilars in rheumatology practice22-24

zz Biosimilars should have lesser cost than the reference/innovator product zz Biosimilars should undergo strict regulatory processes to demonstrate equivalence in safety, efficacy, and immunogenicity with innovator molecules zz In the absence of having undergone strict regulatory processes, such drugs shall only remain as biomimics and should not be referred to as biosimilars zz Biosimilars should be preferably prescribed by their brand name to differentiate them from innovator biologics (also prescribed preferably by their brand name) zz Biosimilars should not be substituted for innovator products, or vice versa, without the knowledge of the prescribing physicians zz All patients receiving biologic drugs, whether innovator or biosimilar, should preferably be enrolled in registries zz Ongoing surveillance should be done to assess any unexpected adverse effects of biosimilars, which might be evident only after marketing EULAR, European League against Rheumatism; GRS, Greek Rheumatology Society; PANLAR, Pan American League of Associations for Rheumatology

Fig. 1: Issues related to biosimilars and their approval processes

in more than 90% patients.21 Neither of these two studies diseases, as of now various international societies have identified any adverse safety signals with adalimumab provided guidelines for the prescription of bio- biosimilar during post-marketing surveillance.20,21 There similar drugs. Box 1 summarizes the relevant information remains an unmet need to generate and publish such real- from the guidelines for biosimilar use provided by world data in a larger number of patients for biosimilar the European League against Rheumatism, the Greek drugs used for different indications in India.22 Rheumatology Society, and the Pan American League of Associations for Rheumatology.23-25 Briefly, these Recommendations for Biosimilar Use in recommendations suggest that biosimilars should be cheaper than reference biologics, share similar safety and Rheumatic Diseases efficacy profile, undergo suitable regulatory approvals Considering the proliferation of available biosimilar before marketing, and be subject to post-marketing drugs worldwide for the management of rheumatic surveillance.

MU-210.indd 1350 29-01-2021 15:24:48 Biosimilars: Bane or Boon for India CHAPTER 210 1351

Conclusion and Future Perspectives 5. Karalis VD. From bioequivalence to biosimilarity: the rise of a novel regulatory framework. Drug Res (Stuttg). 2016;66(1):1-6. Figure 1 summarizes the various issues associated with . 6 Eleryan MG, Akhiyat S, Rengifo-Pardo M, et al. Biosimilars: biosimilar approval and use. Despite potential advantages potential implications for clinicians. Clin Cosmet Investig Dermatol. of biosimilar drugs in terms of cost savings and greater 2016;9:135-42. accessibility with similar efficacy/effectiveness and safety to 7. Agarwal AB, McBride A. Understanding the biosimilar approval and extrapolation process—a case study of an epoetin biosimilar. Crit innovator biologic drugs (provided they have passed through Rev Oncol Hematol. 2016;104:98-107. rigorous regulatory processes), the uptake of biosimilars has not . 8 Alten R, Cronstein BN. Clinical trial development for biosimilars. been uniform. An analysis of a database from the United States Semin Arthritis Rheum. 2015;44(6):2-8. of America reviewed prescriptions of innovator and biosimilar 9. Macdonald JC, Hartman H, Jacobs IA, et al. Regulatory considerations infliximab amongst patients visiting rheumatology practices. in oncologic biosimilar drug development. MAbs. 2015;7:653-61. Only 3.5% patients took up infliximab biosimilar, despite 10. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, et al. Biosimilar this retention rates were similar to innovator infliximab.26 As recombinant human erythropoietin induces the production of discussed earlier, one of the barriers toward uptake or retention neutralizing antibodies. Kidney Int. 2011;80(1):88-92. of biosimilars could be a nocebo effect.4 It is important to 11. Schellekens H. Follow-on biologics: challenges of the “next evaluate such factors and attempt to reduce factors, which generation.” Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association. limit their uptake despite adequate efficacy and safety. This European Renal Association. 2005;20(4):31-6. could be facilitated by conducting qualitative research in this 12. Schellekens H, Lietzan E, Faccin F, et al. Biosimilar monoclonal area. Furthermore, despite some studies showing no definitive antibodies: the scientific basis for extrapolation. Expert Opin Biol cost-saving with biosimilars, it is reasonable to hypothesize that Ther. 2015;15(11):1633-46. in a country, like India, where a majority of health-care settings 13. Bergqvist V, Kadivar M, Molin D, et al. Switching from originator where biosimilars are used is out-of-pocket expenditure,27 infliximab to the biosimilar CT-P13 in 313 patients with inflammatory use of biosimilars shall result in saving of significant costs. bowel disease. Ther Adv Gastroenterol. 2018;11:1756284818801244. Literature suggests that a significant proportion of physicians 14. Tweehuysen L, Huiskes VJB, van den Bemt BJF, et al. Open-label, might not be adequately aware about the nature and utility of non-mandatory transitioning from originator etanercept to biosimilars; hence, better education in this regard might help biosimilar SB4: six-month results from a controlled cohort study. Arthritis Rheumatol (Hoboken, N.J.). 2018;70(9):1408-18. improve the appropriate utilization of biosimilars in the proper 15. Lindström U, Glintborg B, Di Giuseppe D, et al. Treatment setting.3 retention of infliximab and etanercept originators versus their To conclude, biosimilars are a boon for India, particularly corresponding biosimilars: Nordic collaborative observational since they are cheaper and equally efficacious and safe study of 2334 biologics naïve patients with spondyloarthritis. RMD alternatives (after appropriate regulatory approvals) and can Open. 2019;5(2):001079. potentially improve the sustainability of biologic use when 16. Glintborg B, Loft AG, Omerovic E, et al. To switch or not to switch: used appropriately. At the same time, it is necessary to caution results of a nationwide guideline of mandatory switching from about biomimics until they have undergone appropriate originator to biosimilar etanercept. One-year treatment outcomes regulatory approvals to prove their equivalence in safety and in 2061 patients with inflammatory arthritis from the DANBIO efficacy. registry. Ann Rheum Dis. 2019;78(2):192-200. 17. Goll GL, Jørgensen KK, Sexton J, et al. Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator References infliximab: open-label extension of the NOR-SWITCH trial. J Intern Med. 2019;285(6):653-69. . 1 Dörner T, Kay J. Biosimilars in rheumatology: current perspectives 18. Glintborg B, Ibsen R, Bilbo REQ, et al. Does a mandatory non-medical and lessons learnt. Nat Rev Rheumatol. 2015;11(12):713-24. switch from originator to biosimilar etanercept lead to increase in . 2 Handa R. Biosimilars in rheumatology—name changers or game healthcare use and costs? A Danish register-based study of patients changers? J Assoc Physicians India. 2017;65(5):6-8. with inflammatory arthritis. RMD Open. 2019;5(2):001016. 3. Karateev D, Belokoneva N. Evaluation of physicians’ knowledge and 19. Sharma B. Clinical use of ZRC3197 (adalimumab biosimilar) in attitudes towards biosimilars in Russia and issues associated with patients with inflammatory arthritis: a real-life experience. J Assoc their prescribing. Biomolecules. 2019;9(2):57. Physicians India. 2017;65(5):22-5. 4. Kravvariti E, Kitas GD, Mitsikostas DD, et al. Nocebos in rheumatology: 20. Kapoor S, Kaushik VV, Jain R, et al. Real-life tolerability and emerging concepts and their implications for clinical practice. Nat effectiveness of adalimumab biosimilar in rheumatoid arthritis: Rev Rheumatol. 2018;14(12):727-40. ASPIRE registry data. Rheumatol Ther. 2019;6(3):451-9.

MU-210.indd 1351 29-01-2021 15:24:48 1352 SECTION 16 Rheumatology and CTD

21. Kapoor S, Kaushik VV, Jain R, et al. Real-life tolerability and 25. Patrikos D, Boki K, Boumpas D, et al. 2018 Position Paper on effectiveness of adalimumab biosimilar in ankylosing spondylitis: Biosimilars of the Greek Rheumatology Society and Professional the adalimumab biosimilar patient registry data. ACR Open Association of Greek Rheumatologists. Mediterr J Rheumatol. Rheumatol. 2019;1(8):480-4. 2019;30(1):82-3. 22. Misra DP, Agarwal V. Real-world evidence in rheumatic diseases: 26. Bansback N, Curtis JR, Huang J, et al. Patterns of tumor relevance and lessons learnt. Rheumatol Int. 2019;39:403-16. necrosis factor inhibitor (TNFi) biosimilar use across United 23. Kay J, Schoels MM, Dörner T, et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological States Rheumatology Practices. ACR Open Rheumatol. 2020;2(2): diseases. Ann Rheum Dis. 2018;77(2):165-74. 79-83. 24. Kowalski SC, Benavides JA, Roa PAB, et al. PANLAR consensus 27. Misra DP, Sharma A, Agarwal V, et al. Rheumatology science and statement on biosimilars. Clin Rheumatol. 2019;38(5):1485-96. practice in India. Rheumatol Int. 2018;38(9):1587-600.

MU-210.indd 1352 29-01-2021 15:24:48 CHAPTER

211 An Approach to Vasculitis

Packiamary Jerome

Abstract Vasculitis is an immunological disorder leading to inflammation of the vessel wall. The clinical symptoms range from a mild self limiting illness to severe life threatening complication. Vasculitis affects blood vessels of all types and all organs. It may happens as a de novo phenomenon or secondary to other causes like infection, drugs, malignancy, and so on. Vasculitis affects all organs in the body including skin, eye, ear, nose, throat, lungs, heart, joints, etc. The clinical manifestations mimics like that of a viral illness. There will be an elevation of acute phase reactants. Biopsy of the involved organ can give a clue to the diagnosis of vasculitis. Treatment includes supportive care, followed by steroids and immunosuppressants. A comprehensive approach is needed for an accurate diagnosis of vasculitis.

Introduction Classification Vasculitis is a group of disorder characterized by the Vasculitis affects blood vessels of all the types and all the inflammation of the vessel wall. The clinical manifestations organs. Vasculitis should be suspected in any patient with of vasculitis range from a mild self limiting cutaneous unexplained ischemia in the absence of atherosclerosis. involvement to severe life threatening multiorgan Because of the increased vasculature skin is more prone involvement. The diagnosis of vasculitis is difficult as the for vasculitis. The vasculitis is primarily classified into two clinical presentations mimic many other illnesses and the types: diagnosis of vasculitis often gets delayed. A high degree „„ Primary vasculitis: It is presumed to be immune origin. of suspicion, detailed history and systematic physical „„ Secondary vasculitis: It is mainly secondary to other examination may help in arriving at the diagnosis of causes like infection, drugs, malignancy, or idiopathic. vasculitis. Chapel Hill Classification (1993) Epidemiology This classification is currently considered as “Gold The incidence of vasculitis in western population is 20 Standard.” See Table 1. per million per year. The exact incidence and prevalence in India is not available. Among the various types of LIE Classification (1994) vasculitis, the most common is Takayasu’s arteritis and the most uncommon is Temporal arteritis. Wegener’s Primary Vasculitis granulomatosis is more common in north India than „„ Vasculitis of Large, Medium, and Small Vessels: south India. —— Giant cell arteritis

MU-211.indd 1353 29-01-2021 15:24:34 1354 SECTION 16 Rheumatology and CTD

TABLE 1 Classification based on vessel size TABLE 2 Granulomatous and non granulomatous vasculitis

Large vessel zz Giant cell arteritis Granulomatous Non-granulomatous vasculitis zz Takayasu disease Large zz Temporal – Medium vessel zz Polyarteritis nodosa arteritis zz Takayasu vasculitis zz Kawasaki disease arteritis Small vessel vasculitis zz Microscopic polyangiitis Medium – zz Classic PAN zz Wegener’s granulomatosis zz Kawasaki disease zz Churg strauss syndrome Small zz Wegener’s zz Microscopic polyangiitis zz Henoch schonlein purpura granulomatosis zz Henoch schonlein purpura zz Essential mixed cryoglobulinemia zz Churgstrauss zz Essential mixed zz Cutaneous leukocytoclastic vasculitis syndrome cryoglobulinemia

—— Takayasu disease „„ Tumors —— Isolated angiitis of CNS „„ Radiation „„ Vasculitis of Medium and Small Vessels: „„ Extremes of temperature —— Polyarteritis nodosa —— Churg strauss syndrome Approach to Vasculitis —— Wegener’s granulomatosis Vasculitis has multiple presentations. There are no definite „„ Vasculitis of Small Vessels: guidelines or approach to the diagnosis of vasculitis. To —— Microscopic polyangiitis diagnose vasculitis systematic approach is essential with —— Henoch schonlein purpura proper history taking, clinical examination, and laboratory —— Cutaneous leukocytoclastic vasculitis parameters. „„ Miscellaneous: „„ Clinical Findings —— Burger’s disease „„ Laboratory Findings —— Behcet’s disease „„ Radiology —— Cogan’s syndrome „„ Histology —— Good pasteure’s syndrome —— Kawasaki’s syndrome Clinical Manifestations Secondary Vasculitis Vasculitis may present with isolated cutaneous „„ Infection involvement or with a diffuse systemic involvement. „„ Connective tissue disease Systemic vasculitis presents usually around 2nd to 5th „„ Drug hypersensitivity decade except that Henoch schonlein purpura and „„ Essential mixed cryoglobulinemia Kawasaki disease in pediatric age group. Takayasu arteritis „„ Malignancy is common in young females. „„ Hypocomplementemia „„ Post organ transplant General Manifestations The clinical manifestations of vasculitis mimic like that Savage Classification (1997) of a normal viral illness. It includes fever, weight loss, See Table 2. malaise, fatigue, night sweats, generalized ache and a feel of physical unwell. These manifestations are due to the Causes of Vasculitis systemic inflammatory response which is produced by the „„ Immune (idiopathic) release of chemical mediators from the inflamed blood „„ Infection (Bacteria, Fungus, Viral, Rickettsia) vessels. These findings may not occur in patients with „„ Drugs localized form of vasculitis.

MU-211.indd 1354 29-01-2021 15:24:34 An Approach to Vasculitis CHAPTER 211 1355

TABLE 3 Systemic manifestations of vasculitis

Organs involved Manifestations Skin Pupura, Nodules, Plaques, Infarcts, Ulcers, Pyoderma gangrenosum, Widespread skin necrosis, Gangrene, Urticarial wheels Muscles & joints Arthralgia, Arthritis, Myalgia, Weakness Eyes Scleritis (prelimbic area), Ring ulceration, Scleromalacia, Globe perforation, Uveitis and Retinal vasculitis, Loss of vision Ear Recurrent otitis media unresponsive to grommet insertion, Hearing loss, Recurrent ear drum perforation Nose Recalcitrant sinusitis, Nasal septal perforation, Collapsed bridge of the nose Throat Recurrent oral ulcers Airways Tracheal and bronchial stenosis Lungs Infiltrates, Nodules, Cavities, Mass lesions, Abscess, Areas of hemorrhage Heart Coronary arteritis—Kawasaki Pericardial and myocardial involvement at necropsy GI tract Mild abdominal angina, Perforation, Peritonitis, Hemobilia, Hepatic/splenic infarction, Pancreatitis Kidneys Renovascular hypertension, Hematoma around the kidney, Glomerulonephritis, Renal failure, Proteinuria, Microscopic hematuria Reproductive system Testicular infarction, Penile ulcers on glans & shaft, Scrotal ulcers Central nervous system Mononeuritis multiplex, Polyneuritis cranialis, Diffuse brain dysfunction

Systemic Manifestations treatment. The same picture like that of isolated See Table 3. cutaneous involvement to diffuse organ involvement can happen with certain drugs. Some common drugs causing vasculitis are propylthiouracil, antiepileptics Symptoms of Individual Vasculitis like phenytoin, carbamazepine, valproate, antibiotics See Flowchart 1. including macrolides, quinolones, aminoglycosides, penicillins, antitubercular drugs like rifampicin and Red Flag Signs in Vasculitis isoniazid. Several antihypertensives like hydralazine, methyldopa, nifedipine, atenolol, frusemide, diltiazem can „„ Polymyalgiarheumatica—classical of Temporal cause vasculitis. Other drugs include heparin, warfarin, arteritis streptokinase, allopurinol, methotrexate, antidepressants. „„ Jaw claudication during mastication—Temporal Drugs which cause ANCA positive vasculitis include arteritis hydralazine, propylthiouracil, ciprofloxacin, minocycline, „„ Stridor—Wegener’s granulomatosis phenytoin, clozapine, allopurinol, sulfasalazine, „„ Abdominal pain, vomiting, intestinal obstruction, D-penicillamine. bleeding „„ Proteinuria, microscopic hematuria, active urinary sediment in the absence of infection Vasculitis Mimics 2 „„ „„ Mononeuritis multiplex, Polyneuritis cranialis Infections—infective endocarditis, tuberculosis, „„ Acutely progressing skin lesion syphilis, invasive fungal infections, viral/rickettsial infections. „„ Drug induced vasculitis Drug-iduced Vasculitis „„ Cholesterol embolus disease, antiphospholipid Drug-induced vasculitis should never be missed syndrome, sarcoidosis, amyloidosis as the withdrawal of the offending drug is the main „„ Malignancy, atrial myxoma

MU-211.indd 1355 29-01-2021 15:24:34 1356 SECTION 16 Rheumatology and CTD

Flowchart 1: Vasculitis

MU-211.indd 1356 29-01-2021 15:24:35 An Approach to Vasculitis CHAPTER 211 1357

Investigations TABLE 4 ANCA and its specificity

Hematology Pattern Antibodies directed The laboratory picture of vasculitis mimic like that of against an infection. ESR will be elevated. Hematology shows C–ANCA Central, coarse, Anti-serine protease Wegner’s (>90%) dense, granular, 3(PR3) MPA (100%) normocytic normochromic anemia, leukocytosis, and cytoplasmic CSS (50–60%) thrombocytosis. Eosinophilia is most common in Churgh fluorescence 3 strauss syndrome. CRP will be increased. P–ANCA Perinuclear Anti-myeloperoxidase MPA (70–90%) fluorescence (MPO) WG(<10%) Biochemistry Atypical Mixed pattern Lactoferrin, cathepsin Renal function and liver function tests are helpful in ANCA G, elastase, lysozyme determining the extent of the disease, organ damage, and therapeutic intervention. Elevated serum creatinine and During the acute phase of vasculitis, ANCA will be positive decreased creatinine clearance occurs in PAN, GPA, MPA. in very high titres.4 But, ANCA has a poor correlation There will be hypoalbuminemia with hyper­ between tires and clinical disease activity. There are three globulinemia. Gammaglobulinemia is predominantly of different patterns of ANCA shown in Table 4. IgG type but in WG, HSP it is of IgA type. IgE levels are increased in CSS. Imaging Urine Analysis X-ray Chest Urine investigations should be a must to rule out infection. Nodular, cavitating infiltrates is characteristic of Wegner’s Urine may show proteinuria, hematuria, and cylindruria. granulomatosis. Vasculitis must be included in the ANCA associated vasculitis may show active urinary differential diagnosis, when there is unresolving, rapidly sediment with red cell casts. progressive consolidation during adequate antibiotic/ As the treatment of vasculitis involves the use of ATT. Rapidly enlarging parenchymal lesion suggestive immunosuppressants, infections should be ruled out as of pulmonary hemorrhage is characteristic of Wegner’s it can lead to disastrous complications. Procalcitonin is granulomatosis, microscopic polyangiitis. a good diagnostic tool to rule out vasculitic mimic like infection. It will be elevated in infections rather than CT/MRI/PET Scan non-infective inflammatory etiology. But the cost and availability hinders its usage. Apart from the basic workup, The above imaging modalities are used in the diagnosis, specific autoimmune workup has to be done for further delineation of disease extent, identification of biopsy site, evaluation. and monitoring response to therapy. FDG PET scan will help in detection of aortic wall 5 Serology inflammation. Rheumatoid factor is frequently positive in vasculitis. Very high titre of rheumatoid factor is a hallmark of systemic Angiography rheumatoid vasculitis. ANA will be positive in high titres in Angiography defines the extent of disease involvement. SLE, Systemic sclerosis, Sjogrens syndrome, and Overlap It is also useful in classifying the type of vasculitis, syndrome. hepatitis B, hepatitis C is a must to rule out identifying the areas for intervention like angioplasty and classical PAN, cryoglobulinemia vasculitis. Anti GBM stent insertion. It is important in large and medium vessel antibody will be positive in Good Pasteur’s syndrome. vasculitis. It shows the pathognomonic visceral aneurysms in Polyarteritis nodosa. Antineutrophil Cytoplasmic Antibodies (ANCA) ANCA is specific diagnostic tool for diagnosing vasculitis. 2D Echo ANCA is done by indirect immunofluorescence/ELISA. Done to rule out left ventricular dysfunction, myxoma.

MU-211.indd 1357 29-01-2021 15:24:35 1358 SECTION 16 Rheumatology and CTD

Histology be observed within 2 weeks. In urticarial vasculitis dapsone can be combined with indomethacin or Skin Biopsy hydroxychloroquine. Skin biopsy may show features suggestive of inflammation. „„ Hydroxychloroquine (200–400 mg/day): It can be used The same histology may be seen in patients with benign in HUV but not in other small vessel vasculitis. cutaneous vasculitis and SNV. For ideal histopathological „„ Corticosteroids: Low dose steroids (<10 mg on examination, sample should be taken less than 48 hours alternate days) are used to reduce the inflammation of onset of symptoms.6 Nodular skin lesions and involved in patients not responding to steroids in small vessel muscles are preferred sites for PAN. vasculitis. High dose systemic steroids are indicated in severe necrotic/ulcerative cutaneous lesion, acute Renal Biopsy glomerulonephritis, peripheral neuropathy with Granulomatous inflammation in tissue biopsy is suggestive impending palsy and gastrointestinal bleeding. of Wegner’s granulomatosis. Steroid has a good response in HSP in preventing nephritis as well as improves the outcome of existing Nerve Biopsy nephritis. In classic PAN disease control can be achieved with steroids. In HCV associated cutaneous Vasculitis of the vasa vasorum is characteristic of vasculitis, short-term systemic steroids are beneficial mononeuritis multiplex. Sural nerve biopsy is indicated in controlling renal and CNS manifestations.8 Steroids if peroneal neuropathy is seen on electromyography. In should be short term in virus associated vasculitis in giant cell arteritis, Temporal artery biopsy is done. Biopsy order to prevent the risk of viral replication. of subclavian artery is done in Temporal arteritis. Steroids show a good remission. It helps in Mucosa of Sinus and Nose decreasing the infection rate, cumulative dose of cyclophosphamide to achieve remission and decrease As vasculitis is a patchy process, it may be easily missed in rate of secondary malignancy. Temporal arteritis a small biopsy. shows a very good response to steroids. After remission it can be maintained with immunosuppressants like Open Lung Biopsy azathioprine or methotrexate. Systemic steroids are It is a highly rewarding procedure. Pulmonary tissue contraindicated in Kawasaki disease to avoid coronary biopsy is highly specific for Wegener’s granulomatosis. aneurysm formation. Intravenous pulse steroid (methylprednisolone Treatment 1 gm/day for 3 days) therapy is indicated in life threatening organ involvement in diseases like WG, General Measures MPA, CSS. Avoid stress, bed rest, and keep extremities warm. Avoid „„ Cyclophosphamide: Between 2–3 mg/kg/day. It can be smoking in case of severe pulmonary involvement. continued for a year after remission was attained. The Antihistaminics to reduce itching and NSAIDs to decrease side effects are hemorrhagic cystitis, bladder cancer, pain. marrow toxicity. There is an increased occurrence of relapse after withdrawal of the drug. Specific Therapy Alternative regimen is intermittent “pulse” 2 „„ Antibiotics: To control infections according to culture Cyclophosphamide therapy (750 mg/m ) every 2–3 and clinical profile. weeks initially for 2–3 doses every 4 weeks till 6 pulses. „„ Drug: Stop the offending drug in case of drug induced „„ Azathioprine: It prevents recurrence in CSSV either vasculitis. used alone or in combination with steroids. 7 „„ Dapsone: It can be used as the initial agent for „„ Rituximab: Used in frontline drug in patients with HSP. CSVV in the absence of systemic involvement (Dose: Two doses 1 gm each with an interval of 2 weeks. It 50–200 mg/day in divided doses). The response can gives prolonged remission.

MU-211.indd 1358 29-01-2021 15:24:35 An Approach to Vasculitis CHAPTER 211 1359

„„ Antivirals: Interferon α is the preferred drug in hepatitis References C virus associated CV. Significant improvement has 1. Guillevin L, Pragnoux C, Mouthon L, et al. Churg strauss syndrome. been documented with decrease in cryoglobulin Semin Respir Crit Care Med. 2004;25(5):535-45. levels. Ribavirin may be used for treatment as well as in . 2 Naides SJ. Known causes of vasculitis in man. Cleve Clin J Med. prevention of relapse in hepatitis C induced vasculitis. 2002;69(2):15-23. „„ Immunoglobulins: It may be of use in Kawasaki disease. . 3 Mandell BF, Hoffman GS. Systemic necrotizing arteritis. In: Dose: 2 g/kg single dose in combination with aspirin. Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI (Eds). Fitzpatrick’s Dermatology in General Medicine, 6th edition. Early administration prevents the risk of aneurysm New York: McGraw-Hill; 2003. pp. 1718-26. formation. c-PAN was treated successfully with IVIg . 4 Nolle B, Specks U, Ludemann J, et al. Anticytoplasmic antibodies: (2 g/kg over 2–5 days), but relapse rate is common. 1998, their immunodiagnostic value in Wegner’s granulomatosis. „„ Plasmapheresis: It is helpful in cryoglobulinemia and Ann Intern Med. 1989;111:28-40. hepatitis B related classical polyarteritis nodosa in 5. Scmidt WA, Kraft HE, Vorpahl K, et al. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med. 1997;337(19): severe cases refractory to other treatments. 1336-42. „„ Mycophenolate Mofetil: Used in steroid dependent, 6. Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am J steroid resistant cases of HSP, especially with renal Clin Dermatol. 2008;9(2):71-92. complications. 7. Callen JP. Cutaneous vasculitis. What have we learned in the past 20 „„ Deoxyspergualin: Monoclonal antibodies have a years? Arch Dermatol. 1998;134(3):355-7. variable success rate. . 8 Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol. 2003;48(3):311-40. „„ Infliximab: Used in steroid non-responsive necrotizing C S S V.

Conclusion The mortality and morbidity related to vasculitis is mainly due to late diagnosis. As the symptoms are very subtle at the initial stage, there is a delay in the suspicion and diagnosis of vasculitis. Treatment is individualized. A comprehensive approach is needed for successful management of vasculitis.

MU-211.indd 1359 29-01-2021 15:24:36 CHAPTER

How to Manage DMARDs 212 Failure in RA?

N Subramanian

Abstract Rheumatoid arthritis is the most common disease affecting the musculoskeletal system and the immune-inflammatory cascade causes avalanche of detrimental effects to the human systems. Incidence appears to be increasing worldwide and treat to target after early identification of the condition remains the current approach to tackle RA. DMARDs have been the conventional drugs of choice for years together and with the advent of cytokine inhibitors since 2000, prognosis and outlook of immune mediated diseases have improved remarkably. Biologics and Biosimilars have revolutionized the management of RA; however, DMARDs remain the gold standard care for these patients. This article focuses on the management of patients with RA who fail to respond to DMARDs.

Introduction RA occurs frequently in females and around 30 new patients per Lac population each year are diagnosed Rheumatoid arthritis (RA) is the most common of all with RA. Stress and environmental triggers may trigger arthrides and current incidence in India is increasing. the disease onset. About 5% of first degree relatives are The prevalence of RA was available from only four studies, at risk of developing RA.6 Cigarette smoking, coffee, ranging from 0.28% to 0.7%.1 Literature review suggests the and oral contraceptive pills appear to increase the risk RA prevalence, based on the ACR criteria, ranged from 2.8 of development of RA.7 In developing countries due per 1,000 to 7 per 1,000, varying throughout India. Patients to various factors in accessing medical help, delayed with RA taking disease-modifying antirheumatic drugs diagnosis occurs thereby causes functional disability and (DMARDs) ranged from 11% to 100%, with the majority of reduced quality of life.8 the studies reporting proportions more than 75%.1 Various studies report that the DMARDs available to the patients in India include the methotrexate (1990), Diagnosis and Current Management leflunomide (2001), and sulfasalazine (1998).2,3 Shankar et Rheumatoid arthritis, most common form of inflammatory al. reported that on comparing the characteristics among arthritis is usually diagnosed by the presence of joint erosive and non-erosive RA patients in northern India, swelling, raised inflammatory markers, positive anti the median DMARD-naive time period was recorded CCP and imaging evidence of erosions, if required. as 3 years among patients with erosive disease and Ultrasonogram and MRI have been beneficial in identifying 2 years among those without erosive disease.4 Shankar the early changes in the synovium and marrow.9 and colleagues reported again in a study focused on Currently RA is managed using multimodality only female RA patients, the median DMARD-naive time treatment. Diet, counseling, physiotherapy, and period was 3 years.5 occupational therapy compliment drug treatment.

MU-212.indd 1360 29-01-2021 15:24:27 How to Manage DMARDs Failure in RA? CHAPTER 212 1361

Drug management aims to relieve symptoms as soon the use of various biologics in patients with resistant as possible followed by disease modification that slows or rheumatoid arthritis and evidence has shown time stops radiological progression, which is closely correlated and again that Biologics have achieved remission and with progressive functional impairment. improved the quality of life. Disease modifying conventional drugs included Before starting on biologics, we must ensure adequate methotrexate (10–15 mg) given weekly once, sulfasalazine optimization of oral DMARDs with regards to dose, (1–2 gm), leflunomide (10–20 mg) and iguratimod (25–50 compliance, and side effects. Many occasions, patients do mg). Monitoring of bloods for patients while on DMARDs not share the compliance issues, and hence it is important will have to be done every 4 weeks for 2 months and then to explore the problems in taking DMARDs and address once in 3 months. those issues. Biologics are expensive to most patients in India Poor prognostic factors:10 as developing nation; therefore, biosimilars tend to be „„ Persistently moderate or high disease activity despite preferred in patients who can afford. Evidence shows DMARDs approved biosimilars are equally efficacious in the „„ High ESR < CRP management of various inflammatory rheumatic diseases. „„ Presence of high titers of RF and/or ACPA „„ Presence of early erosions Evidence points to reduced compliance to oral Biologics and Biosimilars DMARDs and also effective in two-thirds of patients with We have seen tremendous developments in the use of RA while achieving remission.11 Hence, there is unmet biologics and biosimilars during the last decade and need to improve the patients health, quality of life, and monoclonal antibodies are used in various rheumatic induce remission for the remainder of population with RA. diseases with Treat to Target approach. Biologic therapies have been used in various Causes for DMARDs Failure in RA inflammatory rheumatic diseases like RA, spondyloarthritis „„ Compliance issues (SpA), psoriatic arthritis, ANCA associated vasculitis, and 14-17 „„ Cost factors osteoporosis. „„ DMARD intolerance issues Biosimilars are similar to biologics intended to offer „„ Comorbidities comparable safety and efficacy to the reference molecule. „„ Fear of toxicities and long-term side effects They are often manufactured in cell lines and subject As RA is chronic and long-term drug treatment is to modification like glycosylation. Biosimilars must be necessary, it is important for the physicians to explore shown to be identical to innovator biologics based on data 18 the patients understanding and family support in daily from clinical and analytical studies. life. Compliance can be a problem due to fear of side Methotrexate remains the anchor drug for RA, which effects driven by the society or cost issues or intolerance has been proven to reduce anti-drug antibodies and also 19 to DMARDs. Few patients may have comorbidities that retains radiological remission. might preclude to effective DMARD therapy. Hence, it is The list of currently licensed biologics for use in RA in imperative to explore all these factors before we call as shown in Table 1. DMARD failure. 20 Clinical disease activity should be measured using Pretreatment Screening DAS 28 ESR score—including swollen joint, tender joint, Although biologics and biosimilars can be used in various VAS scale, and ESR. indications in rheumatology, patients need to be screened for TB, Hepatitis, and HIV. They also need to be vaccinated How to Manage the Resistant RA? against hepatitis, chickenpox, influenza, and pneumonia. International guidelines including American College of Screening tests include blood count, CRP, LFT, renal Rheumatology (ACR),12 British Society of Rheumatology function tests, hepatitis B, C screening, mantoux, and and NICE guidance (BSR),13 European League of immunoglobulins for rituximab. ECG and ECHO when Association of Rheumatologists (EULAR)10 have supported appropriate.

MU-212.indd 1361 29-01-2021 15:24:27 1362 SECTION 16 Rheumatology and CTD

TABLE 1 NICE UK approved Biologics for RA

Drugs Mechanism of action Route of administration Frequency Infliximab Chimeric anti TNF IV and Sc After loading, every 8 weeks Etanercept Fusion protein receptor blocker Sc Once weekly Adalimumab TNF blocker Sc Once fortnightly Tocilizumab IL-6 blocker IV and Sc Once a month Sarilumab IL-6 blocker Sc Fortnightly Rituximab CD20 blocker IV Once in 6–12 months Tofacitinib JAk inhibitor Oral Daily Golimumab Human Mab to TNF alpha Sc Once in 4 weeks Certolizumab Pegylated anti TNF SC Once in 4 weeks

Contraindications for use of biologics: References „„ Uncontrolled heart failure, multiple sclerosis, active 1. Handa R, Rao URK, Lewis JFM, et al. Literature review of rheumatoid infections, Hep B, and Hep C positive and untreated arthritis in India. Int J Rheum Dis. 2016;19:440-51. cancers. . 2 Rao UR, Thopu AR, Naidu MU, et al. Early beneficial effects of low „„ Previous septic arthritis, pregnancy, and lactation. dose oral methotrexate in rheumatoid arthritis. J Assoc Physicians „„ Risk of TB has been found to be more in Asian India. 1990;38(5):335-6. countries.21 . 3 Vardhan H, Kabra P, Rohatgi K, et al. Sulphasalazine in the treatment of rheumatoid arthritis in India. J Assoc Physicians India. Nearly a decade of experience in using biologics and 1988;36(5):350. biosimilars has given a wide range of choices for patients 4. hankar S, Grover R, Handa R. Role of anti cyclic citrullinated peptide with RA and those drugs are used in India and gaining antibodies in erosive disease in patients with rheumatoid arthritis. acceptance too.22 Indian J Med Res. 2006;124(6):689-96. . 5 Shankar S, Handa R, Aneja R, et al. Bone mineral density in Indian women with rheumatoid arthritis. Rheumatol Int. 2009;29(4): What do we do if not Affordable to 377-81. Biologics or Biosimilars? . 6 GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause- Recently RA affects women and men of both socioeconomic specific mortality for 240 causes of death, 1990-2013: a systematic groups and being a chronic disease it’s understandable for analysis for the global burden of disease study 2013. Lancet. patients with low income to default on DMARDs. Hence, it 2013;385(9963):117-71. would be prudent to consider low dose long-term steroids 7. Heliövaara M, Aho K, Knekt P,et al. Coffee consumption, rheumatoid and NSAIDs along with monotherapy like methotrexate factor, and the risk of rheumatoid arthritis. Ann Rheum Dis. 2000; for disease remission,23 after having explained the risk for 59(8):631-5. . 8 Haroon N, Aggarwal A, Lawrence A, et al. Impact of rheumatoid diabetes and stomach upset. arthritis on quality of life. Mod Rheumatol. 2007;17(4):290-5. . 9 Xu H, Zhang Y, Zhang H, et al. Comparison of the clinical Conclusion effectiveness of US grading scoring system vs MRI in the diagnosis of early rheumatoid arthritis (RA). J Orthop Surg Res. 2017;12(1):152. DMARDs are effective in RA, but resistant rheumatoid needs 10. Smolen JS, Boers M, Askling J, et al. EULAR recommendations careful approach to devise the management program tailor for the management of rheumatoid arthritis with synthetic and made to the patient and holistic intervention is required that biological disease-modifying antirheumatic drugs: 2019 update includes biologics/biosimilars, physiotherapy, and yoga. Apart Ann Rheum Dis. 2020;79(6):685-99. from disease remission and improved quality of life, we also 11. Pasma A, Boer ED, Timman R, et al. Hazes, Nonadherence to disease need to achieve cardiovascular risk reduction and healthy modifying antirheumatic drugs in the first year after diagnosis: family life. comparing three adherence measures in early arthritis patients. Rheumatology. 2016;55(10):1812-9.

MU-212.indd 1362 29-01-2021 15:24:28 How to Manage DMARDs Failure in RA? CHAPTER 212 1363

12. Singh JA, Saag KG, Bridges JR SL, et al. 2015 American College with delayed etanercept in RA: the VEDERA trial Ann Rheum Dis. of Rheumatology Guideline for the Treatment of Rheumatoid. 2020;79(4):464-71. Arthritis Rheumatol. 2016;68(1):1-26. 18. Ghosh A. Biologics in Rheumatology. Semantic Scholar, 13. NICE guideline. On treatment of rheumatoid arthritis. Available 2012. Available from https://pdfs.semanticscholar.org/d9ab/ from www.nice.org.uk/guidance/ng100 e7d81339ece1f73adef3617868133385c94f.pdf 14. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. 19. Chaturvedi V, Thabah M. Biologics in RA, Medicine update Comparison of etanercept and methotrexate, alone and combined, 2011. Available from http://citeseerx.ist.psu.edu/viewdoc/ in the treatment of rheumatoid arthritis. Arthritis Rheum. download?doi=10.1.1.689.6662&rep=rep1&type=pdf 20. Holroyd CR, Seth R, Bukhari M, et al. The British Society for 2006;54(4):1063-74. Rheumatology biologic DMARD safety guidelines in inflammatory 15. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER arthritis—executive summary. Rheumatology. 2019;58(2):220-6. study: a multicenter, randomized, double-blind clinical trial 21. Malaviya A, Haroon N. Infections associated with the use of biologic of combination therapy with adalimumab plus methotrexate response modifiers in rheumatic diseases: a critical appraisal. Indian versus methotrexate alone or adalimumab alone in patients with J Rheumatol. 2011;6(1 Suppl):99-112. early, aggressive rheumatoid arthritis who had not had previous 22. Nallasivan S, et al. Biosimilars in rheumatology gaining clinical methotrexate treatment. Arthritis Rheum. 2006;54(10):26-37. practice in South India. Annals of Rheumatic Diseases. EULAR 16. Sharma SK. Use of biologics and biosimilars in rheumatology. J Abstract. Available from DOI: 10.1136/annrheumdis-2016-eular.5521. Assoc Physicians India. 2017;65(5 Suppl):9-14. 23. Misra R, Sharma BL, Gupta R, et al. Indian Rheumatology Association 17. Emery P, Horton S, Dumitru RB, et al. Pragmatic randomised consensus statement on the management of adults with controlled trial of very early etanercept and MTX versus MTX rheumatoid arthritis. Indian J Rheumatol. 2008;3(5):S1-16.

MU-212.indd 1363 29-01-2021 15:24:28 CHAPTER

213 IgG4-related Disease

Harpreet Singh, Somdatta Giri, Anju Arya

Abstract IgG4-related disease is a chronic inflammatory condition characterized by tissue infiltration with igG4-secreting plasma cells. It manifests as organomegaly, fibrosis, and organ dysfunction. Elevated IgG4 level in blood gives an important clue to the diagnosis. CD4+ cytotoxic T cells and plasmablasts are central to the pathogenesis, and IgG4 antibody may be a bystander. Biopsy is essential for diagnosis whereas CT, MRI, and PET scan help in defining the extent of the disease. Response to steroid is excellent. Steroid resistant cases are treated with Rituximab.

Introduction RD having atopy had this feature. Recently, researchers noticed that CD4+ cytotoxic T lymphocytes, which are Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) clonally expanded, are found in both peripheral and is a multiorgan immune mediated fibroinflammatory fibrotic lesion of IgG4-RD.3 The cytotoxic T cells release condition of unknown etiology. It was in 2013 in an 1 interleukin-1 (IL-1), transforming growth factor-beta international symposium that term IgG4RD was adopted. (TGF-beta) and Interferon gamma and these cytokines/ chemokines are responsible for increased fibrosis, which Epidemiology is the dominant part of IgG4-RD. Due to the low awareness of disease, there is difficulty in Further, the disease has a sustained CD4+ cytotoxic ascertaining the epidemiology of the disease. IgG4-RD has T cells effect due to continuous antigen presentation by 2 an elderly and male preponderance (Male:Female 3:2). B cells and plasmablast. In addition to CD4+ cytotoxic It tends to involve pediatric age group less commonly. T lymphocyte effect, there is also a follicular helper Presently, there are not much epidemiological studies on T(Tfh) response that is responsible for development IgG4-RD in India. of germinal centers (within the lymph node/involved organ) and production of cytokines (esp IL-4). The Pathogenesis germinal center/cytokine drives the IgG4 class switch, The pathogenesis of IgG4-RD suggests about disease to be producing IgG4 plasmablast and long lived plasma cells.4 autoimmune in nature though incompletely understood. The IgG4 antibodies positivity in IgG4-RD is due to the In the past it was suggested that IgG4-RD to be T helper downregulating response to another primary process. cell-2 (Th-2) mediated condition. But the concept of So IgG4 antibodies are not pathogenic of IgG4-RD, Th-2 memory cells circulating in IgG4-RD presently has rather CD4+ cytotoxic T lymphocytes and plasmablasts been rejected since only a small subset of patient of IgG4- play central role in the pathogenesis.

MU-213.indd 1364 29-01-2021 15:24:22 IgG4-related Disease CHAPTER 213 1365

Clinical Features (esp. patchy meningitis) with or without hypopituitarism, prostatitis, IgG4-related disease of the ovary, constrictive The symptomatology in IgG4-RD is based on organ/s pericarditis, generalized lymphadenopathy are other affected. It is subacute in onset. Clinical presentation in organ presentation described. IgG4-RD is due to the resultant inflammatory infiltration/ fibrosis, which cause the tissue or organ dysfunction. Additionally, tumor like effect may cause obstructive/ Laboratory Tests compressive complications. Despite the multiorgan If there is a suspicion of IgG4-RD one should start work involvement, four clinical types can be more commonly up with routine blood investigations, IgG4 level, imaging identified. These are: studies and finally tissue biopsy, if possible. „„ Group 1: Pancreato-hepatobiliary disease „„ Group 2: Retroperitoneal fibrosis and/or aortitis Blood Tests „„ Group 3: Head and neck limited disease Blood investigations usually reveal hypergamma­ „„ Group 4: Classic Mikulicz syndrome with systemic globulinemia. Peripheral blood shows eosinophilia involvement with elevation of serum IgE (especially in presence of Symptoms of asthma or atopy may be present but fever atopy) and IgG4 level. Serum IgG4 levels can also be is rare. Salivary and lacrimal glands, pancreas, biliary tract, elevated in other conditions, which may mimic IgG4-RD.6 and kidney are commonly involved. Plasmablast concentration is a better marker than IgG4 Auto immune pancreatitis (AIP) is of two types. In the level, as it predicts response to treatment and also relapse.7 context of IgG4-RD, type 1 AIP is generally a pancreatic Hypocomplementemia is particularly common in IgG4- disease and biliary tract involvement (mimicking Primary related kidney disease as well as with mild proteinuria. 5 Sclerosing Cholangitis) in combination. Serum amylase and lipase may be planned if pancreatitis IgG4-RD commonly involves retroperitoneal tissue is suspected. often resulting into fibrosis. This fibrosis may result in obliteration of adjoining structures (aorta and ureter). Imaging Eye involvement (25–50%) in IgG4-RD usually presents On contrast enhanced CT, lesions look homogeneous with as a mass (orbital pseudotumor) due to dacryoadenitis or well-defined margins. MALT lymphoma. MRI (T2-weighted) shows hypointense to isointense Major salivary gland (parotid/submandibular) images depending upon fibrosis/cellularity. involvement mimics Sjögren syndrome, although in IgG4- Increased metabolic activity on FDG-PET/CT helps in RD the symptoms of dryness of eyes and mouth are milder locating the extent of involvement. along with seronegativity for anti Ro/La antibody. Lung involvements are often asymptomatic Histology or may present with respiratory-related symptoms. These symptoms may be due to the alveola/interstitial Findings include lymphoplasmacytic infiltrate, storiform involvement or due to opacities (ground glass/nodular). fibrosis (cartwheel appearance of the arranged fibroblasts 8 The pulmonary manifestations of IgG4-RD may mimic and inflammatory cells) and obliterative phlebitis. In sarcoidosis. addition, an increased number of IgG4-positive plasma Kidney involvements related to IgG4 are tubulo­ cells greater than the cut-off point and elevated IgG4/IgG interstitial nephritis (TIN). Membranous nephropathy cell ratio more than 40% needs to be proven. There may be is much less common. IgG4-related TIN presents with modest tissue eosinophilia. profoundly hypocomplementemia (due to the complement activation by other IgG subclasses—IgG1 or IgG3). Diagnosis Riedels thyroiditis is IgG4-RD of the thyroid gland IgG4-RD is diagnosed by a combination of clinical disorder. (organomegaly), serologic (increased IgG4 level), Cutaneous pseudolymphoma, hepatopathy, gastritis, radiologic (masses on CT, MRI), and pathologic findings sclerosing mastitis, central nervous system involvement (as described above). Biopsy of the involved organ is

MU-213.indd 1365 29-01-2021 15:24:23 1366 SECTION 16 Rheumatology and CTD

crucial for diagnosis. Japanese comprehensive clinical period of 2–3 months. Steroid pulse therapy is considered diagnostic criteria (CCD) 2011,9 are used for diagnosis. for acutely ill patients. Organ-specific diagnostic criteria is used when CCD In the early stage of disease majority responds to criteria does not properly fit in for the diagnosis of IgG4RD. glucocorticoids (decrease in size of mass, betterment of organ function, decrease in IgG4 value), though duration Differential Diagnosis of response remains variable. But disease flare is seen during or after tapering of glucocorticoids. Also, patients The major disorders that should be distinguished from with fibrotic changes respond poorly. IgG4-RD are cancers (pancreatic cancer, cholangio­ carcinoma), primary sclerosing cholangitis, connective Rituximab tissue disease like (Sjögren syndrome, granulomatosis with polyangiitis), Castleman disease, idiopathic RPF, and Patients with multiorgan disease (≥3 organs) or extremely infectious aortitis. high serum IgG4 concentration (>5 times UNL) are very likely to require an agent other than glucocorticoid Treatment alone for induction of remission. Rituximab (anti-CD20 antibody) is effective for both induction and maintenance Treatment should be initiated early to impede the progress in a dose: 1 g IV for a total of 2 doses 2 weeks apart.10 from the inflammatory to fibrotic stage (treatment Rituximab do not directly kill plasma cells as they lack nonresponsive). There is no international consensus on the CD-20 receptor. It acts by depleting the pool of CD20+ treatment guideline at present. The approach to treatment progenitors—either naïve B cells or memory B cells. Thus, in IgG4-RD is discussed here. it wipes out plasmablasts, which have a short lifespan. This loss of plasmablast results in decrease in IgG4 production. Pretreatment Evaluation Evaluation of the extent of disease after establishing the Maintenance Therapy diagnosis is desired before initiating treatment, so baseline High relapse rate is reported with multiorgan disease or investigations are desired pretreatment. These are: extremely elevated IgG4 level. An IgG4-RD responder „„ Complete blood count, RFT, LFT, serum amylase index (RI) has been developed to predict relapse. Low- and lipase, IgG subclass levels—esp IgG4, IgE dose prednisolone (2.5–5 mg/day) needs to be continued concentration, serum C3 and C4 concentration, as maintenance therapy to avoid relapse for a period HbA1c. of at least 3 years, but keeping watch on steroid related „„ Fecal elastase in pancreatic involvement. complications. However, in case of relapse initial dose of „„ Urinalysis to document asymptomatic proteinuria steroid is recommended. related to TIN. Mycophenolate (up to 2.5 g/day) and azathioprine (2 „„ Imaging—CECT/PET scanning to determine the g/kg/day) are the other options for maintenance therapy. extent of disease. Rituximab is very effective as maintenance therapy especially where steroid and other immunomodulator Initial Therapy fails. It has a very low relapse rate. The reason being All symptomatic or those with progressive disease should memory B-cell count appeared to be unaffected by be started on therapy. The others—asymptomatic, non- steroid treatment, therefore partly explaining why the progressive and limited disease need serial watchful maintenance of remission in IgG4-RD often fails during waiting approach. glucocorticoid withdrawal.

Steroid Surgery Glucocorticoids are the drug of choice for initiation, unless Selected patients may require surgery like—hydronephrosis contraindicated. The initial recommended oral dose of due to ureteral obstruction in retroperitoneal fibrosis/ prednisolone for remission induction is 0.6 mg/kg/day for obstructive jaundice due to sclerosing cholangitis requires 2–4 weeks followed by tapering to 2.5–5.0 mg/day over a biliary stenting and drainage/aortic aneurysm in aortitis/

MU-213.indd 1366 29-01-2021 15:24:23 IgG4-related Disease CHAPTER 213 1367

compressive symptoms in Riedell’s thyroiditis/vascular References and organ compression from sclerosing mesenteritis 1. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for requires debulking surgery. the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. 2012;64(10):3061-7. Prognosis 2. Raina A, Yadav D, Krasinskas AM, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J IgG4-RD has a variable course. Some treatment naïve Gastroenterol. 2009;104(9):2295-306. patients are reported to have spontaneous remission 3. Mattoo H, Mahajan VS, Maehara T, et al. Clonal expansion of CD4(+) though short lasting. Whereas, most of them have relapse/ cytotoxic T lymphocytes in patients with IgG4-related disease. J chronic progression at variable rate. Baseline levels of Allergy Clin Immunol. 2016;138(3):825-38. serum IgG4, IgE, and eosinophil serve as markers for . 4 Nirula A, Glaser SM, Kalled SL, et al. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin relapse prediction. Non-treatment results in a significant Rheumatol. 2011;23(1):119-24. morbidity and mortality due to irreversible damage of . 5 Kawaguchi K, KoikeM, Tsuruta K, et al. Lymphoplasmacytic organs and its sequalae because of the associated fibrosis. sclerosing pancreatitis with cholangitis: a variant of primary There is a divided opinion regarding increased risk of sclerosing cholangitis extensively involving pancreas. Hum Pathol. malignancy with IgG4-RD. 1991;22(4):387-95. 6. Khosroshahi A, Walace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4- Conclusion Related Disease. Arthritis Rheumatol. 2015;67(7):1688-99. . 7 Wallace ZS, Mattoo H, Carruthers M, et al. Plasmablasts as a So to conclude, IgG4-RD results in a subacute multiorgan biomarker for IgG4-related disease, independent of serum IgG4 dysfunction/enlargement. The diagnosis is made in a concentrations. Ann Rheum Dis. 2015;74(1):190-5. background of clinical features which shares specific serological . 8 Smyrk T. Pathological features of IgG4-related sclerosing disease. and pathlogical findings. Measurement of plasmablast Curr Opin Rheumatol. 2011;23(1):74-9. concentration correlates better than IgG4 level with disease . 9 Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic activity and is a promising tool to be used in future. A good criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. initial response to steroid is a characteristic behavior of the 2012;22(1):21-30. disease, steroid needs to be tapered over a period of 2 months 10. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy and any relapse or failure to the initial response, Rituximab leads to rapid decline of serum IgG4 levels and prompt clinical holds a good promise. improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62(6):1755-62.

MU-213.indd 1367 29-01-2021 15:24:23 CHAPTER

Treatment of SLE 214 beyond Steroids

Rathindra Nath Sarkar, Rudrajit Paul

Abstract Systemic lupus erythematosus (SLE) is a multi-system connective tissue disorder where immunosuppression is the mainstay of therapy. Steroids, although effective immunosuppressant, have a lot of side effects in the long run. Thus, there is a need of steroid sparing immunosuppressive agents for long-term therapy in SLE. In the first part of this chapter, the conventional steroid sparing drugs like Methotrexate, Cyclosporine, and Mycophenolate, which have been mentioned in the 2019 EULAR guidelines, have been discussed in details. In the second part of this chapter, newer therapies like Voclosporin, anifrolumab, Belimumab, and Baricitinib have been discussed along with the recent clinical trial results. Lastly, newer frontiers of therapy like Glucocorticoid induced leucine zipper (GLIZ) and other experimental drugs have been explained. Discussion of each drug is also associated with mention of the dose and side effects.

Introduction The mainstays of SLE therapy, especially in acute flares, are cyclophosphamide and steroids with steroid sparing Systemic lupus erythematosus (SLE) is a multisystem drugs like Azathioprine and MMF for maintenance. But in connective tissue disorder with considerable mortality spite of quick diagnosis and early treatment, mortality from and morbidity. Since it mainly affects the young adult, SLE is still very high. In 2017, Jorge et al. from the Harvard economically productive, age group, the financial burden Medical School published an article, which showed that of this disease is also significant. Treatment of this disease over 15 years, between 1999 and 2014, the mortality from continues for a long time, sometimes even lifelong. With SLE has not been decreased appreciably.2 As early as in developments in immunology and medical genetics, 2000, researchers from Baltimore, USA, had also shown our understanding of the pathogenesis of this disease that long-term steroid therapy in SLE is associated with is also evolving. This is opening up newer avenues for significant organ damage.3 Thus, it is evident that the therapeutic target. current therapies including steroids are not adequate and SLE is a disorder of autoimmunity. Thus, immuno­ there is a large unmet need in SLE management. suppression or immunomodulation in various forms is the mainstay of therapy. In the early days, the main drug used for this purpose was steroids. While steroid is an effective Conventional Agents immunosuppressant and quite effective in saving lives There are many drugs, besides steroids, which are (especially in acute flares), it also has a lot of side effects in used in SLE. They include hydroxychloroquine (HCQ), the long run1 (Table 1). mycophenolate mofetil (MMF), azathioprine (AZT), Thus, for long-term treatment, steroids are not an cyclophosphamide, methotrexate (MTX), cyclosporine ideal choice. The current SLE guidelines also advice quick (CYC), and tacrolimus (TAC). But they are all not equally tapering of oral steroids to avoid these side effects. effective. HCQ is used as a background therapy but it is

MU-214.indd 1368 29-01-2021 15:24:16 Treatment of SLE beyond Steroids CHAPTER 214 1369

TABLE 1 The different systemic effects of long-term steroid use

Musculoskeletal Endocrine Cardiovascular zz Osteoporosis zz Dysglycemia zz Edema zz Myopathy zz Cushingoid features zz Hypertension zz Osteonecrosis zz Adrenal suppression zz Premature atherosclerosis zz Growth failure in children zz Arrhythmia Ophthalmologic Psychiatric Dermatologic zz Cataract zz Depression zz Acne zz Glaucoma zz Hypomania zz Hirsutism zz Central serous chorioretinopathy zz Sleep disturbance zz Skin thinning zz Akathisia zz Recurrent infections

TABLE 2 2019 EULAR recommendations for non-steroid drugs in SLE

Main target of zz Complete remission treatment zz Low disease activity status (if remission is not obtained) zz Prevention of flares HCQ To be used in all patients (5 mg/kg), long term; if HCQ intolerant, quinacrine MTX To be added when symptoms not controlled with HCQ+GC; once weekly dose; 10–25 mg/week AZT To be added when symptoms not controlled with HCQ+GC; safe in pregnancy; 2–3 mg/kg/day MMF Can be used for both induction and maintenance; not effective in neuropsychiatric lupus; costly; discontinue 6 weeks before planned pregnancy Induction: 3 g/day Maintenance: 1–2 g/day CYC Used in moderate to severe disease activity; avoid in severe renal disease; 1–3 mg/kg/day Cyclophosphamide Mainly used as rescue therapy; gonadotoxic Use either Euro-Lpus or the NIH regimen; avoid after induction dose; oral therapy not recommended IV Ig 1 g/kg/day (1–2 days); mainly used for hemolytic anemia Rituximab RCTs negative; still used off-label; only after failure of above drugs 1000 mg on days 1 and 15; may be repeated after 6 months AZT, azathioprine; CYC, cyclosporine; GC, glucocorticoids; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate.

not effective in acute flares or life threatening conditions. used to help reduce the dose of oral steroids. It is safe in A French study (PLUS) in 2013 found that HCQ is unable pregnancy (in contrast to MMF that must be stopped at to prevent life threatening flares.4 But this does not mean least 6 weeks before conception) but neutropenia may be that HCQ is a non-essential drug in SLE. Continuous a rare, yet serious, adverse reaction. HCQ is effective in preventing flares of skin rashes or There have been very few studies of MTX in SLE. arthritis and this drug should be given to all lupus patients A 2014 systematic review concluded that MTX is effective (Table 2).5 AZT and MMF are both steroid sparing agents. in treating arthritis and mucocutaneous manifestations In the MAINTAIN trial, both of them were found to be of SLE and it also helps to reduce the dose of oral equivalent in preventing relapse of nephritis in SLE.6 In steroids.8 Another study from Germany also depicted the ALMS study, MMF was found to be equivalent to IV that SLE patients, who had not improved despite 6 months Cyclophosphamide in inducing remission in renal flares.7 of oral steroids, did respond to oral MTX 15 mg/week.9 Thus, although cyclophosphamide (in NIH or Euro-Lupus There was not much side effect of MTX in this regimen. protocol) remains the mainstay of rescue therapy in renal However, the efficacy of MTX in lupus nephritis is still flares, MMF may be tried as an alternative. AZT is mainly debatable.10

MU-214.indd 1369 29-01-2021 15:24:16 1370 SECTION 16 Rheumatology and CTD

Cyclosporine, a calcineurin inhibitor (CNI), is another organ failure. However, there are newer therapies in the drug, which has been tried in SLE. Although this is a horizon for SLE. These will be discussed next. good immunosuppressant, it has common side effects A newer analog of CYC, which is in development, is like hypertension and nephrotoxicity, which makes Voclosporin. This drug was first developed in the 1990s, it unsuitable for high-dose therapy. But low-dose but its potential uses are being investigated only recently. maintenance therapy can always be used in SLE. There are In January 2019, Rovin et al. published the results of the very few RCTs with CYC in SLE. These have shown that CYC AURA-LV study, where Voclosporin was used in addition is effective in decreasing proteinuria and improving renal to MMF and rapidly tapering oral steroids for induction function.11 Also, the doses of other immunosuppressants therapy in lupus nephritis.16 The dose of Voclosporin and steroids could be reduced when CYC is used long used was 23.7 mg (low dose) or 39.5 mg (high dose) BD.16 term. Some studies have also shown that CYC may It was found that there was significantly high complete improve the renal histology in lupus patients.11 However, renal remission (CRR) rate in the Voclosporin group (both the serological markers like anti-ds-DNA or complements low and high dose) and this advantage was sustained do not change appreciably with CYC. One reason may at 48 weeks. Very recently, in March 2020, Aurinia be that CYC mainly acts on T-cell subset with very little Pharmaceuticals, the company promoting Voclosporin, effect on the humoral immunity. But despite persistence announced the results of the AURORA study.17 This was of serological abnormalities, clinical improvement occurs a Phase 3 Global RCT, which assessed the efficacy of after CYC use. Voclosporin in addition to MMF and rapidly tapering Tacrolimus, another CNI, till now used in organ oral steroids for induction phase. The results showed that transplant recipients, is now being used in combination Voclosporin was effective in inducing a superior and faster with steroid as well as MMF in refractory proteinuria. renal response. The side effect profile in the AURORA Several small studies have looked into the use of TAC in trial was similar to standard therapy. There was no excess Class III, IV, and V lupus nephritis, both as induction and mortality. In this trial, the dose of Voclosporin was 23.7 mg as maintenance therapy in patients refractory to other BD. Thus, if this new drug is approved, it may be a valuable 12 treatment. Majority were Asian patients. Another study addition in SLE treatment strategy. by Szeto et al. in 18 patients with biopsy proven Class V Type I interferon (INF) is known to be an important lupus nephritis treated with TAC 0.1 to 0.2 mg/kg/day with mediator in the pathophysiology of SLE. Recently, an tapering doses of prednisolone showed 76.2% decrease in inhibitor of the type 1 IFN receptor, Anifrolumab, has been proteinuria compared to historical control group treated developed. In January 2020, Morand et al. published the 13 with cyclophosphamide or azathioprine. Side effect results of a trial of Anifrolumab in active SLE (TULIP-2 profiles are same as CYC with glucose intolerance. trial).18 Anifrolumab (300 mg) was given i.v. every 4 week IV Ig use is still considered experimental in SLE. A for 48 weeks. At 52 weeks, there was significantly more 2014 meta-analysis found that IV Ig is effective in reducing response (assessed by BILAG) in Anifrolumab group 14 disease activity. In some studies, it has also been shown compared to placebo.18 Anifrolumab mainly helped in to be effective as a steroid sparing agent. But till now, only reduction of the glucocorticoid dose and decreasing a few studies have assessed IV Ig for lupus nephritis. The severity of skin disease. But there was not much difference results have been mixed. Thus, it is an uncommon choice in tender joint count. This was the first successful trial of a in acute renal flares. biological drug in SLE since Belimumab almost a decade Table 2 gives a summary of the 2019 EULAR recommen­ ago. The first trial with Anifrolumab was the TULIP-1 dations for the use of non-steroid drugs, as discussed trial, published in the Lancet, in 2019.19 In this trial, the earlier, in SLE.15 primary end point was SLE responder index (SRI-4) at 52 weeks. But this first trial was, however, a failure as there Newer Agents was no difference in SRI-4 between the groups.19 But The drugs discussed above are effective in controlling secondary end-points like reduction in corticosteroid disease activity in many cases but still a large percentage dose and BILAG response were achieved. The researchers of SLE patients continue to have flares and worsening of then quickly published the results of the second trial (as

MU-214.indd 1370 29-01-2021 15:24:16 Treatment of SLE beyond Steroids CHAPTER 214 1371

lupus. Thus, use of the drug in these conditions is not approved. However, as more data becomes available, the recommendations will change. Adverse effect profile of belimumab is also favorable.22 In December 2019, GSK, the maker of belimumab, announced results of the BLISS- LN trial where belimumab was shown to be effective in reducing nephritis. However, the approval of belimumab for treatment of lupus nephritis is still pending. Rituximab is an anti-CD20 antibody, which is an important drug in the treatment of rheumatoid arthritis, some malignancies, and some dermatological conditions. There have been many trials of rituximab in SLE also.23 The Fig. 1: The pathway of action of Belimumab ©RP first few published studies were open, uncontrolled studies. For example, the data published by Leandro et al. in 2002 shows that there were improvements in both clinical and mentioned earlier) where favorable results were shown. laboratory features of SLE after treatment with rituximab Anifrolumab is generally safe for human use. But in 2017, a (500 mg: 2 doses, 2 weeks apart).24 This therapy was used Phase IIb trial with the drug found some excess incidence along with oral steroids and i.v. cyclophosphamide. In 20 of Herpes Zoster and influenza, compared to placebo. 2006, Ng et al. published results of a trial using rituximab The maker of the drug, AstraZeneca, plans to move ahead for refractory SLE.23 They showed that repeated cycles with application for approval although expert opinion is of rituximab may be helpful in difficult-to-treat lupus. still divided about potential efficacy of the drug. However, most of these were clinical open studies. Later, Belimumab, which was approved by the FDA in March two RCTs were undertaken to assess the efficacy of 2011, is the first targeted biological therapy for active rituximab in lupus: LUNAR (renal lupus) and EXPLORER 21 SLE. B lymphocyte stimulator (BLyS) is a costimulator (non-renal). Both trials studied rituximab as an add-on for B-cell survival and function (Fig. 1). It is expressed by therapy to the standard regimen of immunosuppressants a variety of cells like macrophages and is also found in like steroids. Overall, the EXPLORER trial did not reveal soluble form in tissues. BLyS receptor is present on B-cells, any extra benefit of rituximab when added to standard the most important receptor being BR3. Interaction therapy.25 But subgroup analysis revealed significant of BLyS with BR3 prevents apoptosis of B-cells and effect on the primary end point in African-American and promotes autoantibody production. Overexpression of Hispanic patients. Also, there were significant fall in anti- BLyS increases activity of autoreactive B-cells and this is ds-DNA levels and rise in complement levels. The dose of important in the pathogenesis of autoimmune conditions rituximab used was 1000 mg, 2 doses, 14 days apart. Oral like SLE. Belimumab is a human monoclonal antibody steroid was also used in tapering doses. In the LUNAR against BLyS. Binding of belimumab with BLyS prevents trial, patients with Class III or IV lupus nephritis were its interaction with BR3 and thus, reduces B-cell survival randomized to receive rituximab as two 1000 mg doses, 14 and antibody production.21 There have been two Phase days apart, to be repeated after 6 months.26 The primary III trials of Belimumab in SLE: BLISS-52 and BLISS-76. end point of renal response at week 52 was not met. The numbers (52 and 76) indicate the number of weeks The only significant findings were, like EXPLORER trial, for which the study subjects were followed up. While both decrease in anti-ds-DNA and increases in complement the studies demonstrated efficacy of the drug, it was also levels. However, further analysis revealed that patients of seen that the effects were not sustained at 76 weeks.22 African ancestry were more likely to respond to rituximab. The dose of the drug is 10 mg/kg, given i.v. at weeks 0, 2, 4, Also, there was more reduction in proteinuria in the and then monthly. It is used with standard therapies like long term in the rituximab group. So, overall, both these MMF. But one problem of the drug is that, in the trials, it trials were negative. So, although clinical results were was not studied in active lupus nephritis or active CNS encouraging, the randomized trial data did not support

MU-214.indd 1371 29-01-2021 15:24:17 1372 SECTION 16 Rheumatology and CTD

the use of rituximab. This made the use of rituximab for SLE controversial. In 2019, a meta-analysis was published on this topic.27 Twenty-four studies were analyzed. It was seen that, overall, in controlled trials with rituximab, there was more probability of total remission (OR=2.02, 95% CI: 1.23–3.32, P<0.01). Also rituximab is associated with more decrease of proteinuria compared to controls. So, based on this meta-analysis, rituximab may be considered as a viable option in lupus nephritis. The ideal dose is still debated because some of these trials used four 375 mg/m2 weekly doses and some used two 1000 mg fortnightly doses.28 Another anti-CD20 therapy tried in clinical trials for SLE was Ocrelizumab (OZM) (humanized antibody).28 There were two trials: BEGIN (non-renal) and BELONG (Renal). The BEGIN study was stopped early. In the BELONG trial, OZM was used at doses 400 mg or 1000 Fig. 2: Schematic representation of the IL-12/23 pathway in tissue mg on days 1 and 15, and then 4 monthly.28 This trial inflammation ©RP was also stopped early due to increased risk of infections in the group receiving OZM+MMF. The intention-to- Baricitinib is an oral Jak1 and Jak2 inhibitor, which has treat analysis at 32 weeks showed that there was some been approved for use in rheumatoid arthritis. Recently, improvement in renal response in the OZM group, there have been trials of baricitinib in SLE. In 2018, although it did not reach statistical significance. But Wallace et al. published the results of a Phase II trial of the data also showed that there was more probability of baricitinib in SLE patients with arthritis or dermatological response when OZM was combined with the Euro-Lupus manifestations.31 Here, it was found that baricitinib protocol. But as of now, OZM is not a priority candidate significantly improved these manifestations at 24 weeks. drug for lupus trials. The drug is only approved for some Thus, this was a proof of concept that baricitinib can be forms of multiple sclerosis. a viable option for SLE patients in addition to standard Ustekinumab (UKB) is an IL-12/23 antagonist.29 IL-12 is therapy. However, the dose of baricitinib used (4 mg) has involved in activation of various T-cell subsets involved in raised some concerns about the potential for serious side autoimmune response. IL-23 is involved in expansion and effects like neutropenia.32 A Phase 3 trial (SLE-BRAVE-X) survival of pathogenic Th-17 cells. These two pathways are is underway to test the efficacy of baricitinib in SLE. This closely related (Fig. 2). In September 2018, Vollenhoven and similar other studies can clarify the role of this drug et al. published a study of UKB in active SLE in the in the future. Lancet.29 In this study, UKB was given intravenously at the beginning, followed by 90 mg subcutaneously every 8 weeks. Like other biologics, this was also given along New Frontiers with standard therapy. At 24 weeks, there was significantly The most promising new target in controlling inflammation more response with UKB, compared to placebo. The is the glucocorticoid pathway (Fig. 3). same group of researchers published a follow-up study Glucocorticoid-induced leucine zipper (GILZ) is one in 2019.30 In this, it was shown that the benefits of UKB of the GREs in the cell nucleus and it is one of the earliest were maintained at 48 weeks. There were no excess areas in the DNA activated by the hormone.33 GILZ is one malignancies or opportunistic infections. Presently, UKB of the principal mediators of anti-inflammatory activity of is approved for Psoriasis, Ulcerative colitis, and Crohn’s GCs. The most robust evidence of the anti-inflammatory disease. But in the future, this may be a promising therapy activity of GILZ is its effect on the NF-κB/MAPK pathway.33 for active SLE. It directly inhibits NF-κB and prevents induction of the

MU-214.indd 1372 29-01-2021 15:24:17 Treatment of SLE beyond Steroids CHAPTER 214 1373

known like its effect on glycemic status, skin thinning, or cataracts. So, although this is an exciting prospect, its potential for human use is still unknown. Research on GILZ till now is mostly animal model-based.35 Some studies have used truncated regions of the protein while others have used virus vectors with transcription factors to induce GILZ expression in laboratory animals. Presently, two SEGRAM compounds under investigation, RU24858 and ORG 214007-0, are based on targeting GILZ.36 Other newer therapeutic options, which are in various stages of trial, are mentioned here: „„ Tabalumab: Anti-BAFF monoclonal antibody; trials: ILLUMINATE-1 and 2 „„ Epratuzumab: Anti-CD22 antibody; trials: EMBODY 1 and 2 „„ Atacicept: Anti -TACI, tumor necrosis factor Fig. 3: Glucocorticoid cellular pathway transmembrane activator and calcium modulator GR, GC receptor; GRE, GC recognition element and cyclophilin ligand interactor; trials: ADDRESS-II; APRIL-SLE proinflammatory genes. Overall, it shifts the inflammatory „„ Blisibimod: Anti-BLyS antibody; trials: PEARL-SC milieu from Th1 to Th2 response. This molecule is encoded „„ Rigerimod: Peptide derived from a region of U1-70k by the Tsc22d3 gene located on the X chromosome. snRNP protein; immunomodulator binding to MHC- In autoimmune diseases like SLE, it has been shown II; can restore immune tolerance; Phase IIb trial that active disease is associated with lower intracellular encouraging; further trials in progress GILZ levels. This raises the possibility that GILZ deficiency „„ Others: IL-2 therapy, anti CD40 antibody etc. is one of the factors in the pathogenesis of this disease and conversely, GILZ augmentation may be a potential Conclusion therapeutic target. GILZ has effect on Th1, 17 cells and also B-cells.34 Deletion of GILZ in mouse models is associated As the earlier discussion makes clear, there are a lot of options with an increase in B-cells in blood.34 And increased in SLE management. Steroids are needed in the beginning and B-cells means increased autoantibodies. during life threatening flares. But once the patient is stabilized, we should try to shift to the steroid sparing therapies in order As discussed in the introduction section, to avoid the long-term side effects. Choice of steroid-sparing glucocorticoids are associated with a lot of side effects and agents or biologicals should be based on patient profile, this raises a lot of problems in long-term treatment. So, affordability, and organ involvement. it may seem like a paradox that the same glucocorticoid pathway is now the focus of research. But this new research is aimed at other intermediary compounds in References that pathway which can maintain the immunosuppressive . 1 Yasir M, Goyal A, Bansal P, et al. Corticosteroid Adverse Effects. effects without giving rise to the side effects. So, there is a lot StatPearls. [Updated 2020 April 13; Cited 2020 May 23]. Available of research to find glucocorticoid receptor agonists and from https://www.ncbi.nlm.nih.gov/books/NBK531462/ modulators, also called Selective Glucocorticoid Receptor . 2 Jorge AM, Lu N, Zhang Y, et al. Unchanging premature mortality Agonist & Modulator (SEGRAMs).35 GILZ is one such trends in systemic lupus erythematosus: a general population- based study (1999-2014). Rheumatology (Oxford). 2018;57(2): target to bypass the glucocorticoid receptor.35 It has good 337-44. immunosuppressive activity and also, it lacks significant 3. Zonana-Nacach A, Barr SG, Petri M, et al. Damage in systemic lupus metabolic effects. It has neutral or even positive effect on erythematosus and its association with corticosteroids. Arthritis bone density. However, all metabolic effects are still not Rheum. 2000;43(8):1801-8.

MU-214.indd 1373 29-01-2021 15:24:18 1374 SECTION 16 Rheumatology and CTD

. 4 Costedoat-Chalumeau N, Galicier L, Pourrat J, et al. 20. Furie RA, Drappa J, Yoo S, et al. Anifrolumab, an anti-interferon-α Hydroxychloroquine in systemic lupus erythematosus: results of a receptor monoclonal antibody, in moderate-to-severe systemic French Multicentre Controlled Trial (PLUS Study). Ann Rheum Dis. lupus erythematosus. Arthritis Rheumato. 2017;69(2):376-86. 2013;72(11):1786-92. 21. Dubey AK, Sharma KK, Sharma P, et al. Belimumab: first targeted . 5 Aouhab Z, Hong H, Tarplin S, et al. Outcomes of systemic lupus biological treatment for systemic lupus erythematosus. J Pharmacol erythematosus in patients who discontinue hydroxychloroquine. Pharmacother. 2011;2(4):317-9. ACR Open Rheumatology. 2019;1(9):593-9. 22. Navarra SV, Freimuth W, Thomas M, et al. Efficacy and safety of . 6 Houssiau FA, Sangle S, Remy P, et al. Azathioprine versus belimumab in patients with active systemic lupus erythematosus: mycophenolate mofetil for long-term immunosuppression in a randomised, placebo-controlled, phase 3 trial. Lancet. lupus nephritis: results from the MAINTAIN nephritis trial. Ann 2011;377(9767):721-31. Rheum Dis. 2010;69(12):2083-9. 23. Ng KP, Edwards JC, Cambridge G, et al. Repeated B cell depletion in . 7 Isenberg D, Yu X, Wofsy D, et al. Influence of race/ethnicity treatment of refractory systemic lupus erythematosus. Ann Rheum on response to lupus nephritis treatment: the ALMS Study. Dis. 2006;65(7):942-5. Rheumatology (Oxford). 2010;49(1):128-40. 24. Leandro MJ, Edwards JC, Cambridge G, et al. An open study of B . 8 Sakthiswary R, Suresh E. Methotrexate in systemic lupus lymphocyte depletion in systemic lupus erythematosus. Arthritis erythematosus: a systematic review of its efficacy. Lupus. Rheum. 2002;46(10):2673-7. 2014;23(3):225-35. 25. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety . 9 Gansauge S, Breitbart A, Rinald N, et al. Methotrexate in patients of rituximab in moderately-to-severely active systemic lupus with moderate systemic lupus erythematosus (exclusion of erythematosus: the randomized, double-blind, phase II/III systemic renal and central nervous system disease). Ann Rheum Dis. lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 1997;56(6):382-5. 2010;62(1):222-33. 10. Sato EI. Methotrexate therapy in systemic lupus erythematosus. 26. Rovin BH, Furie R, Latinis K, et al. LUNAR Investigator Group: efficacy Lupus. 2001;10(3):162-4. and safety of rituximab in patients with active proliferative lupus 11. Moroni G, Doria A, Ponticelli C. Cyclosporine (CsA) in lupus nephritis: nephritis: the lupus nephritis assessment with rituximab study. assessing the evidence. Nephrol Dial Transplant. 2009;24(1):15-20. Arthritis Rheum. 2012;64(4):1215-26. 12. Wang S, Li X, Qu L, et al. Tacrolimus versus cyclophosphamide as 27. Zhong Z, Li H, Zhou T, et al. Clinical efficacy and safety of rituximab treatment for diffuse proliferative or membranous lupus nephritis: in lupus nephritis. Drug Des Devel Ther. 2019;13:845-56. a non-randomized prospective cohort study. Lupus. 2012;21(9): 28. Reddy V, Jayne D, Close D, et al. B-cell depletion in SLE: clinical and 1025-35. trial experience with rituximab and ocrelizumab and implications 13. Szeto CC, Kwan CH, Lai FM, et al. Tacrolimus for the treatment for study design. Arthritis Res Ther. 2013;15(Suppl 1):S2. of systemic lupus erythematosus with pure class V nephritis. 29. van Vollenhoven RF, Rose S, Lipsky P, et al. Efficacy and safety Rheumatology. 2008;47(11):1678-81. of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with 14. Sakthiswary R, D’Cruz D. Intravenous immunoglobulin in the active systemic lupus erythematosus: results of a multicentre, therapeutic armamentarium of systemic lupus erythematosus: double-blind, phase 2, randomised, controlled study. Lancet. a systematic review and meta-analysis. Medicine (Baltimore). 2018;392(10155):1330-9. 2014;93(16):86. 30. van Vollenhoven RF, Rose S, Gregan I, et al. Maintenance of 15. Fanouriakis A, Moroni G, Mosca M, et al. 2019 update of the efficacy and safety of ustekinumab through one year in a phase EULAR recommendations for the management of systemic lupus II multicenter, prospective, randomized, double‐blind, placebo‐ erythematosus. Ann Rheum Dis. 2019;78(6):736-45. controlled crossover trial of patients with active systemic lupus 16. Rovin BH, Solomons N, Lysenko L, et al. A randomized, controlled erythematosus. Arthritis Rheumatology. 2020;72(5):761-8. double-blind study comparing the efficacy and safety of dose- 31. Wallace DJ, Mosca M, Carmack T, et al. Baricitinib for systemic lupus ranging voclosporin with placebo in achieving remission in erythematosus: a double-blind, randomised, placebo-controlled, patients with active lupus nephritis, Kidney Int. 2019;95(1):219-31. phase 2 trial. Lancet. 2018;392(10143):222-31. 17. Gibson K, Parikh S, Saxena A, et al. AURORA Phase 3 Trial Demonstrates 32. Yuan K, Huang G, Sang X, et al. Baricitinib for systemic lupus Voclosporin Statistical Superiority Over Standard of Care in Lupus erythematosus. Lancet. 2019;393(10170):402. Nephritis (LN). National Kidney Foundation 2020 Spring Clinical 33. Bereshchenko O, Migliorati G, Bruscoli S, et al. Glucocorticoid- Meetings [Conducted online due to Pandemic]. Abstract no# 407. induced leucine zipper: a novel anti-inflammatory molecule. Front [Cited 2020 May 20]. Available from https://casehippo.com/apps/ Pharmacol. 2019;10:308. symposium/national-kidney-foundation-2020-spring-clinical- 34. Jones SA, Toh AEJ, Odobasic D, et al. Glucocorticoid-induced meetings/event/gallery/abstracts?abstractId=1616 leucine zipper (GILZ) inhibits B cell activation in systemic lupus 18. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active erythematosus. Ann Rheum Dis. 2016;75(4):739-47. systemic lupus erythematosus. N Engl J Med. 2020;382(3):211-21. 35. Flynn JK, Dankers W, Morand EF. Could GILZ be the answer to 19. Furie RA, Bruce IN, Manzi S, et al. Type I interferon inhibitor glucocorticoid toxicity in lupus? Front Immunol. 2019;10:1684. anifrolumab in active systemic lupus erythematosus (TULIP-1): 36. Sundahl N, Bridelance J, Libert C, et al. Selective glucocorticoid a randomised, controlled, phase 3 trial. Lancet Rheumatol. receptor modulation: new directions with non-steroidal scaffolds. 2019;1(4):208-19. Pharmacol Ther. 2015;152:28-41.

MU-214.indd 1374 29-01-2021 15:24:18 CHAPTER Gout Is the Only Enemy That I Do Not Wish to 215 Have at My Feet

Anjana Pandey, Ajay Maurya, PK Maheshwari

Abstract Gout or monosodium urate (MSU) crystal arthropathy is a disorder caused by hyperuricemia (serum urate >6.8 mg/dL [>0.4 mmol/L]) that results in the precipitation of monosodium urate crystals in and around joints, resulting into recurrent acute or chronic arthritis. Acute gouty arthritis is characteristically monoarticular and often involves the 1st metatarsophalangeal joint or ankle. Symptoms of gout include acute, severe pain, tenderness, warmth, redness, and swelling. Definite diagnosis requires demonstration of monosodium urate crystals in synovial fluid. This chapter deals with practical approach to diagnosis and management of patients with gouty arthritis.

“Gout is the Only Enemy That I Do Not Wish to Have at My Feet” Epidemiology –Reverend Sydney Smith (1841) The global burden of gout is substantial and seems to be increasing in many parts of the world over the past 50 Introduction years. Gout is most common inflammatory arthritis in Gout is one of the oldest joint diseases known to humanity. men aged more than 50 years. Overall prevalence of gout The term gout originated from the word ‘gutta’ meaning a in adult male is 1–2%. Prevalence in India is 0.1%, but drop (in Latin), as the ancient belief was that the devil is incidence and prevalence have been doubled over past causing the disease by instilling the poisonous humor into two decades probably because of adoption of western 1 the joint of the victim drop by drop. life styles. Gout is rarely seen in premenopausal females Gout is a crystal-deposition disease that results from and children. After menopause, due to lack of estrogens, chronic elevation of uric acid levels above the saturation females are at equal risk of developing gout. point for monosodium urate (MSU) crystal formation. Normal level of serum uric acid (sUA) is 7 mg/dL in males Pathogenesis and 6 mg/dL in females. Initial presentation is mainly The disease often runs in families, but the genetic basis of severely painful episodes of peripheral joint synovitis gout is not well understood. Uric acid is the end product of (acute self-limiting “attacks”) but joint damage and purine degradation in humans. Purines are derived either deformity, chronic usage-related pain, and subcutaneous from the diet or by de novo synthesis. Normal metabolism tophus deposition can eventually develop. Chronic includes conversion of purine first into hypoxanthine in recurrent gouty arthritis leads to development of tophi in presence of enzyme xanthine oxidase, then hypoxanthine the cartilage, tendon, or other soft tissues. into xanthine again in presence of enzyme xanthine

MU-215.indd 1375 29-01-2021 15:24:08 1376 SECTION 16 Rheumatology and CTD

oxidase, and finally xanthine is converted into uric acid of asymptomatic hyperuricemia should be done only which is a trioxypurine. Most of the uric acid is eliminated in those patients who have history of kidney stones and through urine or intestine, the kidney excretes two-thirds, asymptomatic patients with very high sUA, that is, more and rest one-third is excreted via intestine. than 12 mg/dL in men and more than 10 mg/dL in women.

Classification Acute Gouty Arthritis In an acute presentation, patients will notice severe pain, Primary Gout redness, swelling, warmth, and severe tenderness in one or „„ Unknown cause more joints. Symptoms worsen within first 24 hours. Joint „„ Genetic defects in renal handling of urate involvement (in order of decreasing frequency) includes „„ Under secretors (90%) and overproducers (10%) the metatarsophalangeal joint (podagra), forefoot, the ankle, the knee, the wrist, and the fingers.2 In elderly Secondary Gout women, an initial presentation may be acute arthritis „„ Increased urate production: of fingers, having inflamed Heberden’s and Bouchard’s 3 —— Inherited enzyme defects (HGPRTase deficiency, nodes. Untreated acute gout usually resolves within 1–3 glucose-6-phosphatase deficiency) weeks. —— Myeloproliferative disorder —— Psoriasis Intercritical Gout —— Hemolytic diseases This is the period between two attacks of gout. —— Malignancies Approximately 60% of patients have a second attack within —— High purine diet, alcohol the first year, and 78% have a second attack within 2 years. „„ Decreased renal clearance: Only 7% of patients do not have a recurrence within a 10- —— Renal: Chronic kidney disease, polycystic kidney year period.4 disease, lead nephropathy —— Endocrine: Hyperparathyroidism, hypothyroidism, Chronic Tophaceous Gout diabetes insipidus Tophaceous disease is more likely to occur in patients —— Metabolic syndrome: Obesity, hypertension, with the following: a polyarticular presentation, a serum dyslipidemia urate level higher than 9.0 mg/dL, and a younger age at —— Drugs: Diuretics, low dose aspirin, pyrazinamide, disease onset (i.e., 40.5 years or younger).5 The rate of ethambutol, cyclosporine tophi formation correlates with the duration and severity —— Others: Down syndrome, sarcoidosis, toxaemia of of hyperuricemia. The most common sites include the pregnancy joints of the hands and feet. The helix of the ear, the Stages olecranon bursa, and the Achilles tendon are classic, though less common, locations for tophi. Additionally, These are the following four stages of gout: urate deposition in kidneys could lead to nephrolithiasis. „„ Asymptomatic hyperuricemia „„ Acute gouty arthritis „„ Intercritical periods (asymptomatic) Diagnosis „„ Advanced/chronic gout (frequent or constant joint „„ Clinical picture pain, tophi) „„ Crystal examination „„ Serum uric acid Asymptomatic Hyperuricemia „„ Imaging Asymptomatic hyperuricemia is accidental finding and does not warrant urate lowering therapy. Whenever Clinical Pictures patient comes at this stage, meticulous search for other Clinical features helpful in establishing provisional comorbidities must be done and it’s rewarding. Treatment diagnosis of gout:

MU-215.indd 1376 29-01-2021 15:24:08 Gout Is the Only Enemy That I Do Not Wish to Have at My Feet CHAPTER 215 1377

„„ Rapidity (12–24 hours) with which inflammation sign or G sign). These are asymmetrical, eccentric, and reaches maximal away from joint margins. „„ Location: 1st MTP (most common), intertarsal areas, High resolution ultrasound: Detect subclinical Microtophi ankle, knee, insertion of tendoachillis, olecranon and MSU deposit within cartilage of 1st MTP Joint. „„ Monoarticular, intermittent arthritis „„ Spontaneous and complete resolution with or without MRI: It shows bone “edema,” soft tissue pannus, and 8 treatment swelling. „„ Presence of visible or palpable lesion, which by location, texture, or appearance is likely to be tophus Management „„ History of similar episodes in past Aims in the Management of Gout „„ A recent history of trauma, surgery, intercurrent medical illness, or initiation of urate lowering Maintain serum urate in non-tophus gouty arthritis medication or other culprit medicines patients less than 6.0 mg/dL and if chronic tophaceous „„ Presence of hyperuricemia gout then target serum urate level is less than 5 mg/dL to prevent future attacks and reverse prior damage (urate- Joint Aspiration and Synovial Fluid Analysis lowering therapies).

Identifying urate crystals in fluid aspirated from an affected 9,10 joint is the only definitive way to diagnose gout. MSU Non-pharmacological Management crystals are needle-shaped and negatively birefringent on Life style modifications that are important in reducing risk simple polarized light microscopy.6 In an acutely inflamed for gout and/or reducing urate levels (Table 1). joint, these crystals are seen in polymorphonuclear cells.7 Pharmacological Treatment of Acute Gout Hyperuricemia Guidelines Hyperuricemia should never constitute a sole criterion for „„ Affected joints should rest, fomentation should be the diagnosis of gout as hyperuricemia is not present in done. 40% episodes at the time of acute attack. „„ Analgesic and anti-inflammatory drug therapy: commenced immediately and continued for 1–2 Imaging weeks. Joint X-ray: X-ray in gout shows typical punched out „„ Colchicine: Effective alternative (preferably low-dose lesions with scalloping margins/rat bite erosions (Martel’s colchicine)

TABLE 1 Life style modifications important for reducing the risk of Gout

Risk factor Management modality Result Diet Reduction in meat, sea food Decreased risk Increase in low fat dairy intake Decreased risk Increase in protein/complex carbohydrate Decreased risk Reduced fat Decreased risk Reduced beverages beer > distilled spirits Decreased risk > fruit juices > and high fructose corn syrup containing soft drinks Obesity Weight reduction Decreased risk Hypertension (HTN) Reduce BP Decreased risk Culprit drugs Substitute Decreased risk

MU-215.indd 1377 29-01-2021 15:24:10 1378 SECTION 16 Rheumatology and CTD

„„ Urate-lowering drugs (Allopurinol/Febuxostat) should ACTH (Adrenocorticotropic Hormone) not be started during an acute attack. Dose: Between 25 and 50 IU IM/SC; the dose can be „„ In patients already on Allopurinol/Febuxostat, it repeated 12 hourly for 1–3 days in incomplete responders. should be continued with simultaneous treatment for acute attack. IL-1β Inhibitors (Anakinra, Canakinumab, and Rilonacept) Terminating the Acute Gout Flare Highly effective but cost is the constrain. Options: Virtually all anti-inflammatory agents have been used effectively in terminating acute gouty flare.11 Gout Flare Prevention (Prophylaxis) NSAIDs Aim: To decrease frequency and severity of acute gout flares, especially when starting urate lowering therapy. „„ Most useful agent is indomethacin in a dose of 50 mg 6 hourly for 2 days followed by 50 mg 8 hourly. Once Options: pain settles, it can be reduced further to 25 mg 8 hourly. „„ Oral colchicine (in dose of ≤0.6 mg twice daily after Other nonsteroidal anti-inflammatory drugs (NSAIDs) meals) that can be used are naproxen (750 mg/day), etoricoxib „„ NSAIDs-benefit not established but can be used in (120 mg/day), and diclofenac (50 mg 8 hourly). a patient who is intolerant or in whom colchicine is „„ NSAIDs are relatively contraindicated in patients ineffective suffering from renal diseases, peptic ulcer disease, „„ IL-1β inhibitors? (Rilonacept; canakinumab) congestive heart failure, and hypertension. Prophylaxis is initiated when urate-lowering therapy „„ Aspirin used for cardiovascular prophylaxis can be is started and stopped when sUA is in goal range for more continued during acute attack under cover of anti- than or equal to 6 months. inflammatory agents. Management of Recurrent, Intercritical, and Colchicine Chronic Gout11 Colchicine is the ideal drug where diagnosis of gout is not Goal of therapy: sUA < 6 mg/dL confirmed, the latest recommendation is to start 2 tablets Candidates for chronic therapy of 0.5 mg colchicine as loading dose then 0.5 mg, 1 hour „„ Patients with two or more attacks per year later, if needed, one more tablet of 0.5 mg after 12 hours, „„ Patients with tophi then continue colchicine in a dose of 0.5 mg twice or thrice „„ Patients with renal insufficiency a day after meals until acute attack resolves.12,13 „„ Patients with uric acid stones Corticosteroids Co-prescribe: Colchicine or NSAIDs for 6 months Preferred only when NSAIDs or colchicine are Avoid use of medications that can increase sUA. contraindicating or ineffective especially useful in Example: diuretics, ethambutol, pyrazinamide, etc. polyarticular gout following surgery, renal or hepatic Options: Agents that promote uric acid excretion insufficiency, or congestive heart failure. (uricosuric agents): Intraarticular: 40 mg of triamcinolone acetonide or 80 mg „„ Probenecid of depot steroid (methylprednisolone). „„ Sulfinpyrazone „„ Benzbromarone Parenteral (intramuscular or intravenous): Methyl­ „„ Losartan prednisolone (100–150 mg), the dose can be repeated 12 „„ Fenofibrate hourly for 1–3 days in incomplete responders. „„ Vitamin C Oral: 20 mg of prednisone BD, taper to stop within 7–10 Agents that inhibit uric acid formation (xanthine days. oxidase inhibitors):

MU-215.indd 1378 29-01-2021 15:24:11 Gout Is the Only Enemy That I Do Not Wish to Have at My Feet CHAPTER 215 1379

„„ Allopurinol transplant patient. It is safe in mild to moderate renal „„ Febuxostat impairment and rarely cause hepatotoxicity. Therefore Agents that convert uric acid to allantoin (uricase SGOT/SGPT level should be monitored before starting preparations): and after continuation of therapy. „„ Rasburicase: Recombinant fungal uricase (Aspergillus Dosage is 50–200 mg daily. flavus and Candida utilis) Angiotensin receptor blocker: Particularly losartan is „„ Pegloticase: Pegylated, recombinant, porcine-baboon also uricosuric drug and acts by inhibiting renal tubular uricase reabsorption of urate. Biologic Agents Fenofibrate: It is a lipid lowering agent and has uricosuric effect. „„ Anakinra „„ Canakinumab Vitamin C: It can be given in a dose of 8 gm/day in divided „„ Rilonacept dosage. „„ Start uric acid lowering therapy 1–2 weeks after inflammation has settled Urate-lowering Strategies „„ Initial long-term treatment of recurrent uncomplicated Inhibit uric acid formation by inhibiting xanthine oxidase gout (Allopurinol or febuxostat) inhibitors: „„ Allopurinol 14 Uricosuric Agents „„ Febuxostat Promote uric acid excretion Allopurinol: Approved at daily doses of 100–800 mg/day „„ Hyperuricemia results from impaired renal uric acid but 95% of dosing is at less than or equal to 300 mg/day clearance in 90% of gout patients (under-excretors of and at this dose it sub-optimally controls the sUA levels uric acid). (only 21–55% patients achieve target sUA of 6 mg/dL). „„ Candidate patients for uricosurics are fewer than with Factors contributing to low dosing of allopurinol:15,16 xanthine oxidase inhibitors. „„ Intolerance (~10%) including rare but life-threatening Limitations of uricosurics: rashes and hypersensitivity syndrome. „„ Ineffective in renal insufficiency (CrCl < 50–60 mL/ „„ Dosage reduction recommended with impaired renal min) function. „„ Results in modest decrease in sUA „„ Minimal RCT evidence for safety and efficacy of „„ Risk of uric acid stone formation allopurinol at doses more than 300 mg/day. „„ Cannot be used in presence of renal calculi Unmet needs with Allopurinol therapy:14 Probenecid: Achieve satisfactory control in 60–85% of „„ Under-dosing: Only 53% patients achieve target sUA patients and dose is 1–2 gm/day. with the commonly used dose of 300 mg/dL Sulfinpyrazone: It is uricosuric agent and related to „„ Intolerance and allergies: Drug rash with Eosinophilia phenylbutazone. It also acts as antiplatelet agent. and Systemic symptoms (DRESS) Therefore, should be used cautiously in patients, who are „„ Dosing adjustment required in comorbid conditions: anticoagulated, have bleeding problem and peptic ulcer Kidney impairment disease. „„ Drug: Drug interactions (Azathioprine, Mercaptop- The dosage is 100–200 mg twice a day and increase up urine) to 800 mg/day. The above factors result into non-compliance (50%) Patients on uricosuric drugs are advised to maintain and treatment failure. high urine flow (plenty of water intake) to avoid Febuxostat: Non-purine, selective xanthine oxidase/ crystallization of uric acid in renal tubules. xanthine dehydrogenase inhibitor, which completely Benzbromarone: Potent uricosuric drug used in patients inhibits activity of XO enzyme by obstructing substrate with no improvement with allopurinol and in renal binding.17-19

MU-215.indd 1379 29-01-2021 15:24:11 1380 SECTION 16 Rheumatology and CTD

Indications 3. Brauner DJ, Sorensen LB, Ellman MH, et al. Rheumatologic diseases. „„ Chronic management of hyperuricemia in patients In: Cassel CK (Ed). Geriatric Medicine: An Evidence Based Approach, with gout 4th edition. New York: Springer-Velag; 2003. pp. 573-619. . 4 Gutman AB. The past four decades of progress in the knowledge „„ Allopurinol hypersensitivity/intolerance/failure of gout, with an assessment of the present status. Arthritis Rheum. „„ CKD, where the reduced allopurinol dose sub- 1973;16(4):431-45. optimally controls the sUA levels . 5 Nakayama DA, Barthelemy C, Carrera G, et al. Tophaceous Initiate dose is 40 mg OD. Monitor the sUA after gout: a clinical and radiographic assessment. Arthritis Rheum. 2 weeks. If target (<6 mg/dL) not achieved, shift to the 1984;27(4):468-71. . 6 Dieppe PA. Investigation and management of gout in the young higher dose (80 mg or 120 mg). and the elderly. Ann Rheum Dis. 1991;50(4):263-6. Adverse effects: Transaminitis, acute gouty flares, . 7 American College of Physicians. PIER: Physicians’ Information and myocardial infarction, immune hypersensitivity reaction, Education Resource. Available from http://pier.acponline.org/ index.html [Accessed February 12, 2007]. renal failure, angioedema. 8. Yu JS, Chung C, Recht M, et al. MR imaging of tophaceous gout. AJR Am J Roentgenol. 1997;168(2):523-7. Uricase 9. Levinson W, Cohen MS, Brady D, et al. To change or not to change: „„ Apes and human beings lack uricase “sounds like you have a dilemma.” Ann Intern Med. 2001;135:386-91. „„ Uricase converts insoluble uric acid into soluble 10. Emmerson BT. The management of gout. In: Hochberg MC, Silman AJ, Smolen J, et al. (Eds). Rheumatology, 3rd edition. Edinburg: allantoin Mosby; 2003. pp. 1929-36. 11. Jordan KM, Cameron JS, Snaith M, et al. British Society for Recombinant Uricase Rheumatology and British Health Professionals in Rheumatology Rasburicase: Short-term use in tumor lysis syndrome guideline for the management of gout. Rheumatology. but unsuitable in gout due to short half-life and 2007;46:1372-4. immunogenicity. 12. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour Pegloticase: It is useful in treatment failure cases and outcome of the first multicenter, randomized, double-blind, tophi. Dose 8 mg IV every 2 weeks. Limitation is infusion placebo-controlled, parallel-group, dose-comparison colchicine reactions, attenuation of clinical response due to study. Arthritis Rheum. 2010;62:1060-8. development of inhibitory antibodies. 13. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Conclusion Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1312-24. Hyperuricemia and gout are not synonymous. Do not treat 14. Angelo LG, Kenneth GS. Febuxostat: evidence for its use in the asymptomatic hyperuricemia. At least half of patients who treatment of hyperuricaemia and gout. Core Evid. 2010;4:25-36. present with an initial attack of gout take a diuretic or other 15. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. medication predisposing to hyperuricemia or gout. Do not Description and guidelines for prevention in patients with renal start a urate-lowering agent during an acute attack of gout; insufficiency. Am J Med. 1984;76:47-56. however, do not stop one if the patient is already taking it and 16. Reinders, MK, Haagsma C, Jansen TL Th A, et al. A randomised experiences a recurrence. Limiting allopurinol to 300 mg/day is controlled trial on the efficacy and tolerability with dose escalation insufficient to control gout in many cases; aim should be “dose to of allopurinol 300-600 mg/day versus benzbromarone 100-200 target.” Febuxostat represents an effective treatment option to mg/day in patients with gout. Ann Rheum Dis. 2009;68:892-7. allopurinol may be considered as first-line treatment. Biologics 17. Becker MA, Schumacher HR, Espinoza LR, et al. The urate- are very effective option, but cost is the maim constraint. lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. References 18. Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat 1. Chopra A, Patil J, Relwani J, et al. Prevalence of rheumatic diseases compared with allopurinol in patients with hyperuricemia and in a rural population in western India: aWHO-ILAR COPCORD study. gout. NEJM. 2005;353:2450-61. J Assoc Physicians India. 2001;49:240-6. 19. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering 2. Harris MD, Siegel LB, Alloway JA, et al. Gout and hyperuricemia. Am therapy on the velocity of size reduction of tophi in chronic gout. Fam Physician. 1999;59(4):925-34. Arthritis Rheum. 2002;47:356-60.

MU-215.indd 1380 29-01-2021 15:24:11 CHAPTER

Liver Dysfunction and NAFLD in 216 RA: Is MTX Really a Culprit?

Kartik Nikhil Balankhe, Rishabh Ramu Nayak, Pulin Kumar Gupta

Abstract There is an increased risk of nonalcoholic fatty liver disease (NAFLD) in patients with rheumatoid arthritis (RA) as they share a lot of risk factors. Methotrexate (MTX), which used in the treatment of RA, further increases the risk as it is a potentially hepatotoxic drug. NAFLD related to MTX is believed to be related to folate antagonism and genetic (C677T) polymorphism. However, there is an absence of significant clinical and histological hepatic worsening seen. Possible options for monitoring include LFT, USG, Fibroscan, and scoring systems (like NAFLD-LFS). Transaminase elevations more than three times the normal values are rarely seen. If at all seen, then the first step should be to evaluate for other confounding causes. If MTX is the likely culprit, it should be withheld and restarted after normalization of values. As a last resort, other DMARDs can be tried; however, it should always be the priority to keep the patient on MTX for as long as possible as it is the sheet anchor drug in RA. Also, MTX is associated with a possible reduction in serious outcomes and has a possible protective effect from the development of metabolic syndrome.

Introduction of India ranges from 9% in rural to 32% in urban.2 Asians have been found to have increased body fat as compared Rheumatoid arthritis (RA) is the most common to the Europeans even at the same BMI, and hence Indians autoimmune inflammatory arthritis. It is an autoimmune are at a greater risk for NAFLD even if having a normal disorder that can also affect other parts of the body 3 including the liver. There is an increased risk of BMI. Reasons for this may be environmental factors and nonalcoholic fatty liver disease (NAFLD) in patients lifestyle related factors like high-fat diets and reduced with RA as they share a lot of risk factors including physical activity. Having said that, still most of the Indian obesity, and hence metabolic syndrome (MS) (which patients with NAFLD are overweight or obese instead of is worsened with decreased physical activity in these having a normal BMI as per the Asian-Pacific criteria even individuals). Additionally, a known hepatotoxic drug, though they do not have the typical morbid obesity that is 4 methotrexate (MTX), which is commonly used and is the seen among the Western patients. However, in the Indian sheet anchor drug in the treatment of RA is associated with patients with NAFLD, a lower prevalence of full-blown transaminitis as a common side-effect. NAFLD represents MS is found, which may be related to the lower frequency a spectrum of liver disorders ranging from steatosis, of hypertension and diabetes in patients presenting with steatohepatitis (NASH), cirrhosis to primary liver cancer. raised transaminases.5 In Indian patients with RA, the In the United States, about 29% of patients with RA have prevalence of MTX-associated NAFLD with transaminitis mild to moderate NAFLD and about 1.4% have advanced is found to be 4.7%. This is somewhat lower than expected disease.1 The prevalence of NAFLD in general population and the methodological, ethnic, and genetic variations may

MU-216.indd 1381 29-01-2021 15:24:00 1382 SECTION 16 Rheumatology and CTD

be a reason for this discrepancy in the actual prevalence. strong trend toward less of these serious outcomes in However, the simultaneous use of other disease-modifying them although not reaching the statistical significance. antirheumatic drugs (DMARDs), viz. hydroxychloroquine However, the reason for this possible decrease in serious and sulfasalazine, does not influence the development outcomes is not completely apparent.15 Similarly, a of NAFLD with transaminitis.6 In another Indian study negative association between MTX use and the presence involving patients with RA on low-dose weekly MTX, only of the MS is noted, which suggests that MTX may protect 7.5% were reported to have significant hepatic fibrosis as against its development. This protective effect of MTX is assessed by transient elastography.7 There is a paucity of not a result of generic anti-inflammatory effect, but is likely Indian studies regarding the exact prevalence of NAFLD to be drug-specific. This is not observed with any of the (by USG) in patients with RA and on MTX. other DMARDs.16 A similar association was also observed in another study where it was assumed to be purely due Role of MTX in Pathogenesis to the anti-inflammatory effect of MTX, although no data was presented to support it.17 The lower incidence of MS As per the studies conducted in the past, the duration in patients on MTX may be seen because of the increased of MTX therapy and especially its cumulative dose physical activity in these individuals as the disease activity seems to be significantly related to the occurrence of 6,8 reduces with appropriate treatment; however, further transaminitis. However, some also suggest that these studies are needed to confirm this postulate. factors are not significant in causing transaminitis in patients with RA.9 NAFLD associated with MTX therapy is believed to be Clinical Features related to folate antagonism in the hepatic tissues which Patients with RA and NAFLD are structurally obese with have high cellular turnover. The probable mechanism clinical evidence of insulin resistance in the form of involves inhibition of purine metabolism, polyamine acanthosis nigricans. They are usually asymptomatic but synthesis, and homocysteine metabolism.10 The liver may have occasional pain in the right upper quadrant biopsy specimens taken from the patients with RA have of abdomen due to underlying hepatomegaly. Clinical demonstrated hepatic folate deficiency and accumulation features due to enzyme derangements in the form of loss of MTX-polyglutamates in the liver.11 The other culprit of appetite, nausea, or vomiting are minimal because the mechanism is related to the genetic polymorphism degree of transaminitis is generally minimal despite the in metabolic pathways of MTX that resulted in the usage of MTX. Peripheral stigmata of chronic liver disease development of NAFLD. It is also been reported that C677T and portal hypertension may be rarely seen in advanced polymorphism increases the likelihood of MTX toxicity.12,13 cases (especially those with cirrhosis). However, studies with new grading systems and electron microscopy now have confirmed an absence of significant Diagnosis changes in liver histology in patients with RA on long- Since the diagnosis of NAFLD does not require any term MTX. There is also an absence of clinical meaningful invasive testing, it is always to be done by history, physical hepatic worsening. Hence, it is safe to use MTX for a long examination, liver imaging, and few blood tests (to exclude 14 duration with proper monitoring in patients with RA. In other liver diseases). History of ethanol consumption of fact, many of the serious adverse effects of MTX are linked more than 20 g/day in men and more than 10 g/day in with the daily dosing or very higher doses (e.g., 100 mg/ women exceed the diagnostic cut-off for NAFLD. Intake week) that was used in the past but with the introduction of medications causing hepatic steatosis and other causes of lower and less frequent dosing regimens, these toxicities of liver injury like viral hepatitis, autoimmune diseases are hardly seen nowadays. must be excluded.18 Suspicious drugs including other co-prescribed hepatotoxic drugs in the treatment of RA Does MTX have a Protective Role? like leflunomide and NSAIDs19,20 and other risk factors It is seen that the patients with RA on MTX, despite having for NAFLD like obesity, diabetes, dyslipidemia, insulin minor or major transaminitis, do not have an increased resistance, and MS may also increase the likelihood of risk of liver cell failure, cirrhosis, or death. There is a NAFLD and they always need careful evaluation.21 Hence,

MU-216.indd 1382 29-01-2021 15:24:00 Liver Dysfunction and NAFLD in RA: Is MTX Really a Culprit? CHAPTER 216 1383

it is not easy to simply mark the liver dysfunction to MTX Treatment in patients with RA. The treatment of patients on MTX having abnormal Liver biopsy is the gold standard to confirm NAFLD, but liver functions is always debatable. The first step in the it is an invasive procedure and is very rarely advocated for treatment of such patients is to confirm the diagnosis. the confirmation of MTX related liver disease. It is rather Evaluation for other potential causes, viz. NSAIDs, alcohol indicated for the evaluation of other potential causes of intake, obesity, and viral infections (hepatitis B and C), transaminase elevations when the diagnosis is unclear.15 should be done. If no other cause is identifiable, then A pretreatment liver ultrasound for patients at a high risk look at the degree of transaminitis. Though transaminase of NAFLD is recommended. Some centers even advocate a elevations do not necessarily correlate with the stage of pretreatment liver biopsy for high-risk patients but is not NAFLD, most of the guidelines have used this to monitor recommended as a blanket practice in current guidelines.22 hepatotoxicity with MTX. The estimation of baseline Amongst the imaging modalities, ultrasonography of the transaminase levels before MTX initiation is important. A liver is the imaging modality of choice for screening of person who previously had elevated transaminase levels fatty liver.23 This has almost replaced the liver biopsy for which has not changed after starting MTX should not be the diagnosis of NAFLD.21 Another imaging technique is subjected to further evaluation. Transaminase elevation the Transient Elastography or Fibroscan, which measures more than three times the upper limit of normal is often an liver fibrosis by measuring liver stiffness. The other newer indication to withdraw the drug. In case of persistent low- imaging modalities like Shear-Wave Elastography (SWE), grade elevations particularly if the trend is for a progressive Proton Magnetic Resonance Spectroscopy (¹H-MRS), MRI increase in the levels, the dose of MTX is reduced and using Proton Density Fat Fraction (MRI-PDFF), and MRE further investigations are carried out simultaneously.15 (MR Elastography) are also useful in diagnosis. Some also advise stopping MTX when transaminases rise Biochemical tests include estimation of alanine to more than two times the upper normal limit.22 However, transaminase (ALT) and aspartate transaminase (AST) irrespective of the cut-off used, it may be restarted at a levels in serum. Elevation of ALT and AST is very modest lower dose after normalization of these levels. Some other and usually less than twice normal. As the hepatic modalities like USG of the liver, Fibroscan, and Scoring fibrosis increases, the ALT levels fall further downward. Systems (FIB-4 Score) can also be used to identify NAFLD The characteristic AST to ALT ratio of less than 1 seen in and adjust the MTX dose accordingly.25 Now, the question NASH patients reverses as the disease progresses toward that still remains unanswered is—“What if significant 24 cirrhosis. Another biochemical test is the detection transaminitis reappears even with lower doses of MTX of Cytokeratin/Keratin (CK/K) 8 and 18 fragments in and other causes being ruled out?”. Here, we would like blood, which can help to differentiate NASH from simple to suggest switching to other DMARDs or biologicals after steatosis or normal liver more reliably than serum considering the patient’s disease severity, accessibility, 18 aminotransferase levels. and affordability. However, we need to remember that Many other noninvasive scoring systems can also be MTX is still the sheet anchor drug in RA with probably very useful. The FIB-4 score, for instance, is a valuable being the most efficacious, cheapest, easy for compliance, tool to diagnose liver disease in patients with RA treated and with minimal side effects (especially at a dose less 25 with long-term MTX therapy. Hepatic indices like than 25 mg/week, which is far lower than the doses used NAFLD-Liver Fat Score (NAFLD-LFS), Hepatic Steatosis in oncology) and its substitution should only be done if we Index (HSI), Fatty Liver Index (FLI), and Aspartate are left with no options to continue with it. aminotransferase-to-Platelet Ratio Index (APRI) are handy and easy tools and can also reliably predict Conclusion NAFLD.26,27 The Lipid Accumulation Product (LAP) is also useful to identify people with hepatic steatosis.28 Out of MTX is a proven culprit causing liver dysfunction in patients the four NAFLD prediction scores—FLI, HSI, LAP, and with RA, although with the current data and studies available, it NAFLD-LFS; it is found that the NAFLD-LFS score has the is seen in very few patients. It is mostly transient and not always best noninvasive prediction value for NAFLD.29 Contd...

MU-216.indd 1383 29-01-2021 15:24:01 1384 SECTION 16 Rheumatology and CTD

Contd... 10. Van Ede AE, Laan RFJM, Blom HJ, et al. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. clinically significant enough to warrant its discontinuation. Semin Arthritis Rheum. 1998;27(5):277-92. To exclude the other causes of NAFLD should be the first 11. Kremer JM, Galivan J, Streckfuss A, et al. Methotrexate metabolism rule. Pharmacogenetic approaches may help to optimize the analysis in blood and liver of rheumatoid arthritis patients: treatment with MTX but this may not be feasible in all parts of association with hepatic folate deficiency formation of the world before starting this drug. Fibroscan is not available at polyglutamates. Arthritis Rheum. 1986;29(7):832-5. all the diagnostic centers and the poor people of developing 12. Hider SL, Morgan C, Bell E, et al. Will pharmacogenetics allow better countries like India cannot go for repeat evaluations. At prediction of methotrexate toxicity and efficacy in patients with the most, what we can use for serial monitoring are LFTs, RA? Ann Rheum Dis. 2003;62(6):591-2. noninvasive scores (NAFLD-LFS), and occasional USGs of the 13. Urano W, Taniguchi A, Yamanaka H, et al. Polymorphisms in the liver for serial evaluation of such patients. MTX is and will methylenetetrahydrofolate reductase gene were associated with always remain the gold standard backbone therapy in RA, and both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis. Pharmacogenet Genomics. hence we recommend continuing therapy and keeping such 2002;12(3):183-90. patients on a regular follow-up to pick up liver dysfunction 14. Kremer JM, Kaye GI, Kaye NW, et al. Light and electron microscopic early. Careful small dose adjustments should be done as per analysis of sequential liver biopsy samples from rheumatoid the laboratory parameters and prompt reintroduction of the arthritis patients receiving long-term methotrexate therapy drug should be done as soon as the picture normalizes. To followup over long treatment intervals and correlation with clinical summarize the protective effect of MTX, it is associated with a and laboratory variables. Arthritis Rheum. 1995;38(9):1194-203. possible reduction in serious outcomes and also has a possible 15. Conway R, Low C, Coughlan RJ, et al. Risk of liver injury among protective effect from the development of MS. methotrexate users: a meta-analysis of randomised controlled trials. Semin Arthritis Rheum. 2015;45(2):156-62. 16. Toms TE, Panoulas VF, John H, et al. Methotrexate therapy References associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60—more than just an 1. John A. Incidence and factors associated with the development anti-inflammatory effect? A cross sectional study. Arthritis Res Ther. of non alcoholic fatty liver disease (NAFLD) among patients with 2009;11(4):R110. rheumatoid arthritis [Internet]. Walden University; 2016. Available 17. Zonana-Nacach A, Santana-Sahagún E, Jiménez-Balderas from https://scholarworks.waldenu.edu/dissertations/1972 FJ, et al. Prevalence and factors associated with metabolic 2. Chatterjee A, Basu A, Chowdhury A, et al. Comparative analyses of syndrome in patients with rheumatoid arthritis and systemic lupus genetic risk prediction methods reveal extreme diversity of genetic erythematosus. J Clin Rheumatol. 2008;14(2):74-7. predisposition to nonalcoholic. J Genet. 2015;94(1):105-13. 18. Abdelmalek M, Diehl A. Nonalcoholic fatty liver diseases and 3. Alberti KGMM, Zimmet P, Shaw J, et al. The metabolic syndrome—a nonalcoholic steatohepatitis. In: Kasper D, Hauser S, Jameson J, new worldwide definition. Lancet. 2005;366(9491):1059-62. Fauci A, Longo D, Loscalzo J (Eds). Harrison’s Principles of Internal 4. Duseja A. Nonalcoholic fatty liver disease in India—is it different? Medicine, 19th edition. McGraw-Hill Education; 2015. pp. 2054-7. Trop Gastroenterol. 2006;27(4):142-6. 19. Lee SW, Park HJ, Kim BK, et al. Leflunomide increases the risk of 5. Duseja A, Das A, Das R, et al. The clinicopathological profile of Indian silent liver fibrosis in patients with rheumatoid arthritis receiving patients with nonalcoholic fatty liver disease (NAFLD) is different methotrexate. Arthritis Res Ther. 2012;14(5):R232. from that in the West. Dig Dis Sci. 2007;52(9):2368-74. 20. Park JS, Park MC, Park YB, et al. Concurrent use of methotrexate and 6. Sakthiswary R, Chan GYL, Koh ET, et al. Methotrexate-associated celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis nonalcoholic fatty liver disease with transaminitis in rheumatoid patients with subclinical reduced kidney function. Clin Rheumatol. arthritis. Sci World J. 2014;2014:823763. 2014;33(10):1415-23. 7. Kumar A, Vasdev V, Manrai M, et al. Assessment of hepatic fibrosis 21. Anstee Q, Jones D. Liver and biliary tract disease. In: Walker B, in patients with rheumatoid arthritis on long-term methotrexate Colledge N, Ralston S, Penman I (Eds). Davidson’s Principles therapy using transient elastography. Indian J Rheumatol. & Practice of Medicine, 22nd edition. Edinburgh: Churchill 2018;13:246-51. Livingstone, Elsevier; 2014. pp. 921-88. 8. Sotoudehmanesh R, Anvari B, Akhlaghi M, et al. Methotrexate 22. Labadie JG, Jain M. Noninvasive tests to monitor methotrexate- hepatotoxicity in patients with rheumatoid arthritis. Middle East J induced liver injury. Clin Liver Dis. 2019;13(3):67-71. Dig Dis. 2010;2(2):104-9. 23. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and 9. Mori S, Arima N, Ito M, et al. Non-alcoholic steatohepatitis-like reliability of ultrasonography for the detection of fatty liver: a meta- pattern in liver biopsy of rheumatoid arthritis patients with analysis. Hepatol. 2011;54(3):1082-90. persistent transaminitis during low-dose methotrexate treatment. 24. Ralston S, Mclnnes I. Rheumatology and bone disease. In: Walker PLoS One. 2018;13(8):1-16. B, Colledge N, Ralston S, Penman I (Eds). Davidson’s Principles

MU-216.indd 1384 29-01-2021 15:24:01 Liver Dysfunction and NAFLD in RA: Is MTX Really a Culprit? CHAPTER 216 1385

& Practice of Medicine, 22nd edition. Edinburgh: Churchill 27. Kruger FC, Daniels CR, Kidd M, et al. APRI: a simple bedside marker Livingstone, Elsevier; 2014. pp. 1057-136. for advanced fibrosis that can avoid liver biopsy in patients with 25. Miyata M, Kuroda M, Unakami M, et al. Validation of the fibrosis-4 NAFLD/NASH. South African Med J. 2011;101(7):477-80. (FIB-4) index in the diagnosis of liver disease of rheumatoid 28. Bedogni G, Kahn HS, Bellentani S, et al. A simple index of lipid arthritis patients treated with methotrexate. Mod Rheumatol. overaccumulation is a good marker of liver steatosis. BMC 2019;29(6):936-42. Gastroenterol. 2010;10(1):98. 26. Kahl S, Straßburger K, Nowotny B, et al. Comparison of liver fat 29. Cheung CL, Lam KSL, Wong ICK, et al. Non-invasive score identifies indices for the diagnosis of hepatic steatosis and insulin resistance. ultrasonographydiagnosed non-alcoholic fatty liver disease and PLoS One. 2014;9(4):94059. predicts mortality in the USA. BMC Med. 2014;12(1):154.

MU-216.indd 1385 29-01-2021 15:24:01 CHAPTER

Sexual Dysfunction in 217 Rheumatic Diseases

Vinod Ravindran

Abstract Normal sexual function is an important component of both physical and mental well being. Sexual dysfunction, therefore can negatively impact an individual’s quality of life. Sexual dysfunction, though not uncommon, remains an under-explored area in Rheumatology. There are several unique factors contributing to the burden of sexual dysfunction in patients with rheumatic diseases. This review discusses pertinent areas which need specific exploration and offers some thoughts on how to effect the therapeutic aspects of management of this challenging comorbidity in day-to-day rheumatology practice.

Introduction Barriers in exploring/assessing sexual dysfunction BOX 1 Sexual health has been defined by the World Health in rheumatic diseases Organization (WHO) as a state of physical, mental, and social well-being in relation to sexuality and it has zz I am too busy! (time constraints) been recognized as an important factor having positive zz Discomforting subject (uneasiness) 1 or negative effects on an individual’s quality of life. zz Why should I screen? (ambivalence in role) The WHO has recognized sexual health as extremely zz How should I do it? (competence) important necessitating well thought out plans to pick zz Not a part of standard assessment, so not important! (perceived them up, start preventive measures and appropriate lack of applicability) 1 management. Sexual functioning is a neglected area zz Gender of the patient (barrier in communication) of quality of life in patients with rheumatic diseases and is not routinely addressed.2 In a study assessing the impact of an outpatient based intervention to improve rheumatologists’ identification of sexual health aspects effective communication between not only female in younger individuals with chronic rheumatological patient-male clinician but also between female patient- 5 diseases found that only few rheumatologists ever female clinician. In addition, generally, cultural, religious screen their patients for sexual activity.3 Existing health and social barriers in India make the due assessment of assessment questionnaire and other quality of life tools for sexual dysfunction difficult, irrespective of the gender. rheumatological conditions do not assess sexual function.4 Shame and frustration prevent patients to volunteer Box 1 lists some of the barriers in effective exploration of the information on issues with sexual function. In the sexual dysfunction. addition, lack of specific exploration of this area by Female preponderance of several rheumatic diseases clinicians leads to under diagnosis of sexual dysfunction is an additional factor which may negatively impact in such patients.

MU-217.indd 1386 30-01-2021 14:03:16 Sexual Dysfunction in Rheumatic Diseases CHAPTER 217 1387

The Sexual Response Cycle arthritis, and lupus or deformities of rheumatoid arthritis) may compound the problems. In some conditions such as Sexual function and the amount of satisfaction derived ankylosing spondylitis erectile dysfunction has not only from it have the potential to positively or negatively impact been reported to be common but appears linked to high on the individual’s quality of life. Sexuality encompasses disease activity.12 the sexual act itself, self-image and the valorization of self and the relationship with the partner. The sexual response cycle is comprised6-8 of four distinct stages namely, desire, Drugs and Sexual Dysfunction excitation, orgasm, and resolution. In either gender it Pharmacological treatment of the rheumatic diseases leads to simultaneous and often reciprocal physiological fortunately does not cause major issues as far as the changes allowing and facilitating the sexual act and its sexual function is concerned. There are reports though desirable outcomes. Any disturbances in sexual desire of reversible erectile impotence caused by methotrexate, and physiological aspects of the sexual response cycle sulfasalazine, and hydroxychloroquine. Commonly may cause distress and inter-personal difficulties and are used non-steroidal anti-inflammatory agents such labeled as sexual dysfunction.8 as diclofenac, misoprostol, and naproxen may cause interference with libido. Antidepressant medications used Mechanisms of Sexual Dysfunction in in the management of fibromyalgia can lead to loss of desire and difficulty with orgasm. Steroids can contribute Rheumatic Diseases to sexual dysfunction in multiple ways including weight Sexual dysfunction in rheumatic diseases is fairly common gain, abnormal hair growth, altered body image, psychosis, 9-11 ranging from 36% to 70%. The factors responsible for and striae.13 aberration in the sexual function in rheumatic diseases can be categorized into physical and physiological Determinants of Sexual Dysfunction domains (Table 1). In chronic rheumatic diseases both Factors such as severity of the disease, levels of fatigue, these domains are likely to play a part. Conditions such amount of pain, physical limitations, act of weight bearing as osteoarthritis, ankylosing spondylitis and rheumatoid leading to discomfort, perception of self, self-esteem arthritis may prevent attaining relevant sexual positions. and emotional status, adverse effects of pharmacologic Both primary and secondary Sjogren’s syndrome can agents, effects of surgery, and fatigue either alone or in lead to vaginal dryness, which may cause dyspareunia. combination can determine the sexual function in an Pain and fatigue which are a part and parcel of many individual with rheumatic disease.14 Generally speaking, rheumatic diseases also contribute. Altered body image irrespective of the gender of the patient, sexuality is and apprehension about partner’s interest (for example, adversely impacted by level of pain, depression, and due to skin involvement in systemic sclerosis, psoriatic physical limitations. A recent study looking into sexual functioning and its correlates in premenopausal married Indian women with SLE found that dose of glucocorticoids, Contributors to sexual dysfunction in rheumatic TABLE 1 diseases active lupus, presence of depression and anxiety, and marital satisfaction were all important determinants.15 Physical domains Psychological domains zz Heightened tactile sensitivity zz Diminished sense of sexual attractiveness Strategies to Manage Sexual Dysfunction zz Reduced endurance zz Reduced sexual desire General Measures zz Impaired motion zz Reduced satisfaction Irrespective of the type of rheumatic diseases, some zz Vaginal dryness zz Issues with sexual arousal practical tips to patients and partners are useful and easily zz Inability to have an orgasm zz Impaired sensation of penile adoptable (Box 2). They are generally aimed at relaxation, turgidity relieving pain and improving function. A useful resource zz Inability to have erection zz Inability to achieve orgasm in this regard is a booklet entitled “Sex and Arthritis” by the

MU-217.indd 1387 30-01-2021 14:03:17 1388 SECTION 16 Rheumatology and CTD

UK based charity Arthritis Research UK.16 This booklet has entitled “PLISSIT” (for Permission, Limited Information, information on sexual positions which most couples can Specific Strategies and Intensive Therapy).17 Details 17 try and improve with a little experimentation and open of this approach have been provided in Table 2. It is discussion, and adopt positions that are comfortable and envisaged that an ideal team would have psychologist, enjoyable for both partners.16 physiotherapist, occupational therapists, sex therapist, rheumatologist, and gynecologist.8 Specific Approaches It is also important to consider hip or knee arthoplasty as per the clinical needs. Both knee and hip arthroplasty Panush and colleagues have proposed a specific have been shown benefit in improving sexual function multidisciplinary approach to manage sexual dysfunction mainly by allowing the liberty to choose a greater variety of sexual positions.18,19

BOX 2 Measures for patients and their partners Conclusion zz Resting before sexual activity Sexual dysfunction in rheumatic diseases is though common, zz To ease stiffness of joints and muscles use of warm shower or hot bath, use of electric blanket remains either under or undiagnosed and affect men as well as women.20 It is important for the clinicians to be aware of this zz Taking analgesics and anti-inflammatory drugs as required well important aspect of their patients’ well-being and be prepared before sexual act to explore it further and offer appropriate management with zz Massage during the act of foreplay to help relax muscles and the help of a multidisciplinary team. joints zz Supporting joints appropriately by rolled up blankets or pillows zz Use pacing as a strategy to avoid fatigue References zz Use specific positions to reduce discomfit . 1 World Health Organization, Department of Reproductive Health and Research. Defining sexual health. Report of a technical consultation on sexual health, 28-31 January 2002. World Health Organization, Geneva. 2006;35. Available from https://www.who. PLISSIT approach to managing sexual dysfunction TABLE 2 int/reproductivehealth/publications/sexual_health/defining_sh/ in rheumatic diseases* en/. 2020 Step Actions . 2 Helland Y, Garratt A, Kjeken I, et al. Current practice and barriers to the management of sexual issues in rheumatology: results of a Permission zz Demonstrating readiness for the dialogue and survey of health professionals. Scand J Rheumatol. 2013;42(1):20-6. exploration of patients’ issues related to sexual function . 3 Britto MT, Rosenthal SL, Taylor J, et al. Improving rheumatologists’ zz Conveying that patient’s issues related to screening for alcohol use and sexual activity. Arch Pediatr Adolesc sexual function are manageable Med. 2000;154(5):478-83. zz Exploring the issues related to sexual function 4. Gossec L, Paternotte S, Aanerud GJ, et al. Finalization and validation by involving the patient and his/her partner of the rheumatoid arthritis impact of disease score, a patient- derived composite measure of impact of rheumatoid arthritis: a Limited zz Seeking and furnishing information about information sexual dysfunction EULAR initiative. Ann Rheum Dis. 2011;70(6):935-42. zz Trying to establish the cause of sexual . 5 Kedia AK, Ravindran V. Influence of gender on autoimmune dysfunction rheumatic diseases. In: Sharma S (Ed). Women’s Health in Autoimmune Diseases. Singapore: Springer Nature; 2020. pp. 17-28. Specific zz Considering specific interventions to address 6. Levin RJ, Both S, Georgiadis J, et al. The physiology of female sexual strategies the cause/reason of sexual dysfunction, e.g. considering hormonal replacement, review function and the pathophysiology of female sexual dysfunction of exiting pharmacological treatment, stress (Committee 13A). J Sex Med. 2016;13(5):733-59. management, measures to reduce vaginal . 7 Alwaal A, Breyer BN, Lue TF, et al. Normal male sexual function: dryness, and approaches listed in Box 2 emphasis on orgasm and ejaculation. Fertil Steril. 2015;104(5): 1051-60. Intensive zz Involving a sex therapist as required therapy . 8 Almeida PH, Castro Ferreira Cd, Kurizky PS, et al. How the 17 rheumatologist can guide the patient with rheumatoid arthritis on *Table created based on information available from Panush et al. sexual function. Rev Bras Reumatol. 2015;55:458-63.

MU-217.indd 1388 30-01-2021 14:03:17 Sexual Dysfunction in Rheumatic Diseases CHAPTER 217 1389

. 9 Abdel-Nasser AM, Ali EI. Determinants of sexual disability and 15. Pinto B, Grover S, Dhooria A, et al. Sexual functioning and its dissatisfaction in female patients with rheumatoid arthritis. Clin correlates in premenopausal married Indian women with systemic Rheumatol. 2006;25(6):822-30. lupus erythematosus. Int J Rheum Dis. 2019;22(10):1814-9. 10. Josefsson KA, Gard G. Women’s experiences of sexual health when 16. Available from https://www.versusarthritis.org/media/1330/sex- living with rheumatoid arthritis—an explorative qualitative study. and-arthritis-information-booklet.pdf. 2020. BMC Musculoskelet Disord. 2010;11:1-8. 17. Panush SR, Mihailescu GD, Gornisiewicz MT, et al. Sex and arthritis. 11. Helland Y, Kjeken I, Steen E, et al. Rheumatic diseases and sexuality: Bull Rheum Dis. 2000;49(7):1-4. disease impact and self-management strategies. Arthritis Care Res. 18. Kazarian GS, Lonner JH, Hozack WJ, et al. Improvements in sexual 2011;63(5):743-50. activity after total knee arthroplasty. J Arthroplasty. 2017;32(4):1159-63. 12. Santana T, Skare T, Delboni VS, et al. Erectile dysfunction in 19. Laffosse JM, Tricoire JL, Chiron P, et al. Sexual function before ankylosing spondylitis patients. Int Braz J Urol. 2017;43(4):730-5. and after primary total hip arthroplasty. Joint Bone Spine. 13. Dua A, Das P, Ravindran V. Glucocorticoids: a review of its adverse 2008;75(2):189-94. effects including bone loss. Indian J Rheumatol. 2019;14(5):90-8. 20. Perez-Garcia LF, Te Winkel B, Carrizales JP, et al. Sexual function and 14. Tristano AG. Impact of rheumatoid arthritis on sexual function. reproduction can be impaired in men with rheumatic diseases: a World J Orthop. 2014;5(2):107-11. systematic review. Semin Arthritis Rheum. 2020;50:557-73.

MU-217.indd 1389 30-01-2021 14:03:18 CHAPTER

Interpretation of Common 218 Investigations in Rheumatology

Renu Saigal, Amit Kansal, Vikram Raj Jain

Abstract Autoimmune rheumatic diseases (ARDs) are multiple; diagnosis of these diseases depends on meticulous history, physical examination, and investigations. These diseases are characterized by inflammation, autoimmunity, and the presence of autoantibodies. Inflammation is assessed by acute phase reactants, viz. high leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, alkaline phosphatase, and by low albumin levels. Various antibody tests are done to support the clinical diagnosis of ARDs, e.g., rheumatoid factor (RF), antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), etc. Positivity does not always confirm the diagnosis as false positivity may be seen in normal persons, in non-rheumatic diseases and other ARDs, e.g., ANA may be positive in rheumatoid arthritis (RA) patients and RF may be present in systemic lupus erythematosus (SLE); therefore, clinical setting and pre-test probability have to be considered before ordering or interpreting positive tests. Few patients may be suffering from ARD, but the tests may be negative. Therefore, a good correlation between clinical features and laboratory tests has to be done before the final diagnosis.

Introduction phosphatase. Negative APRs are also there, which decrease with inflammation, for example, albumin. Rheumatic diseases are multiple and are characterized by ESR—ESR increases with age, upper limit for males inflammation, autoantibodies and damage to the organs. is half the age while in females half of sum of age plus 10 To evaluate autoimmune rheumatic diseases (ARDs) it (so for 70 year male it is 35 while in female will be 40).1 is very important to elicit a good detailed history and ESR is also high in anemia, infections, cancer, pregnancy, perform meticulous examination of patient before getting trauma, kidney disease, obesity, and with high fibrinogen tests done. Ordering an “Arthritis Panel” should be avoided levels. Its rise and fall may be delayed with the onset and as tests of inflammation are non-specific and may be remission of inflammatory disease, respectively. elevated in other conditions also. Similarly autoantibodies CRP—It is more consistent than ESR as it rises and falls may be falsely positive in normal persons and in patients quickly. It gets elevated within 4 hours of inflammation with non-rheumatic diseases. One antibody may be or infections and peaks at 24–72 hours. In systemic lupus present in other ARDs too, for example, rheumatoid factor erythematosus (SLE) CRP is usually normal except in (RF) and antinuclear antibody (ANA). presence of infection, severe serositis, or synovitis. Tests to Assess Inflammation Autoantibodies In response to inflammation there is increase in serum concentrations of acute phase reactants (APRs) Rheumatoid Factor (RF) (Table 1), for example, erythrocyte sedimentation rate It is an autoantibody directed against the Fc (constant) (ESR), C-reactive protein (CRP), ferritin, and alkaline region of the IgG molecule. Antibody may be of various

MU-218.indd 1390 29-01-2021 15:23:51 Interpretation of Common Investigations in Rheumatology CHAPTER 218 1391

TABLE 1 Acute phase reactants TABLE 2 RF positivity in non-rheumatic diseases

Laboratory Abnormality Autoimmune rheumatic Condition Frequency of RF (%) test disease (ARD) Aging (>50 years) 5–25 CBC zz Anemia zz NCNC, IDA Infection zz Leukocytosis zz Active inflammation Bacterial endocarditis* 40 zz Leucopenia zz SLE, MAS zz Thrombocytosis zz Active inflammation Hepatitis C* 40–76 ESR zz Increased zz In most ARD Tuberculosis 15 zz zz Low MAS Syphilis* 8–37 CRP zz Increased zz In most ARDs except Parasitic diseases 10–25 (>6 mg/L) in SLE Leprosy* 70–80 zz Infections Other viral infections* 15–20 S. Alkaline zz Increased Indicates active phosphatase inflammation Pulmonary disease Sarcoidosis* 5–30 S. Ferritin zz Increased zz Active inflammation zz Very high zz SoJIA, ASD, MAS Interstitial pulmonary fibrosis 10–50

S. Albumin Decreased In inflammation Silicosis 30–50 Asbestosis 30 ASD, Adult onset still disease; CBC, Complete blood count; CRP, C-reactive protein; ESR, Erythrocyte sedimentation rate; IDA, Iron Miscellaneous diseases deficiency Anemia; MAS, Macrophage activation syndrome; NCNC, Primary biliary cirrhosis* 45–70 Normocytic normochromic; SoJIA, Systemic onset juvenile idiopathic arthritis. Malignancy* 5–25 After multiple immunizations 10–15 isotypes, IgM, IgG, and IgA. IgM RF is routinely measured *May cause polyarthritis resembling RA. The best-documented examples of viral infection (in addition to hepatitis B and C) are using latex agglutination while all the three isotypes rubella, mumps, influenza, HIV, dengue, coxsackie virus, EBV and CMV are measured using nephelometry and enzyme linked infections, Herpes virus, and parvovirus. Major parasitic diseases are immunosorbent assay (ELISA). RF is present in 70–80% Chagas’ disease, Leishmaniasis, onchocerciasis, and schistosomiasis. B cell neoplasms are the most common malignancies. patients of RA. Titer usually correlates with the severity of rheumatoid arthritis. RF may be present in normal persons and in various other rheumatic diseases (Sjögren Antinuclear Antibody (ANA) syndrome 75–95%, Mixed cryoglobulinemia type II 100%, The term antinuclear antibody describes a variety of SLE 15–35%, mixed connective tissue disease 50–60%, autoantibodies that react with multiple intracellular Systemic sclerosis 20–30% ANCA associated vasculitis, antigens such as nuclear antigens (DNA, histone, Dermato-/polymyositis 20%, Systemic vasculitides 5–20%, nucleosomes, centromere, topoisomerase, etc.) and in 2 etc. and in non-rheumatic conditions as well (Table 2). some patients against cytoplasmic antigens (e.g., Jo1 or histidyl tRNA synthetase, mitochondria, smooth muscle Anti-citrullinated Peptide Antibody (ACPA) cell, etc.). It is an antibody against citrullinated peptide (post- ANA should be done by indirect immunofluorescent translationally modified citrulline). It is better test for assay (IIFA) using human epithelial cells (HEP2) derived RA as compared to RF as it is 98% specific for RA but its from human laryngeal carcinoma cell line as substrate. It sensitivity is equal to RF, that is, 70–80% and it is costly. is reported positive in 1: 80 or more dilution, depending Seroprevalence of ACPA was found in 10% of other on the kit manufacturer’s recommendations. ANA may rheumatic diseases3 and in non-rheumatic diseases. be positive in 20% of normal sera, majority of which are Presence of ACPA may antedate RA by several years and is against dense fine speckled 70 antigen (DFS-70). Anti- indicative of severe erosive disease. DFS antibody may be diagnosed by immunoadsorption

MU-218.indd 1391 29-01-2021 15:23:52 1392 SECTION 16 Rheumatology and CTD

Flowchart 1: ANA (IFA) algorithm „„ Anti-dsDNA: There are three methods of assessment: —— IIF using crithidia Luciliae—It uses unicellular hemoflagellate, staining of its kinetoplast is seen with serial dilutions of plasma by IIF technique. —— ELISA—Since titers are available by this method, so it is good for monitoring disease activity. Specificity for SLE by this method is 70%.5 It also correlates moderately well with active nephritis. —— Radioimmunoassay assay (Farr Assay)—Seldom used because of difficulty in disposing of radioactive material. „„ Anti-Sm and Anti-U1 RNP: Both antibodies produce coarse speckled pattern (Fig. 1B) in IIF assay and corresponding antigens (Sm and U1 Ribonucleoprotein) colocalize in small nuclear ribonucleoprotein particles (sn RNP). Anti-Sm Ab is found in 20–30% patients of SLE and is specific for SLE ANA, antinuclear antibody; ENA, extractable nuclear antigen; unlike anti-dsDNA, it may remain positive in remission AID, autoimmune disease also. Anti-U1 RNP is present in all patients of mixed connective tissue disease (MCTD) and few patients of method, which is seen in normal persons with false- SLE (Table 4). positive ANA (Flowchart 1).4 „„ Anti-Ro (SSA) & Anti-La (SSB): Autoantigen Ro60 ANA should always be ordered when there are is localized to nucleus and nucleolus, while Ro52 is clinical features of connective tissue disease like fever, localized to cytoplasm. So, if Anti-Ro52 (in cytoplasm) photosensitivity, alopecia, mucosal lesions, serositis, is present ANA may be reported negative by HEP2 IIF nephritis, Raynaud’s phenomenon, inflammatory method. Anti-Ro52, if present in juvenile idiopathic polyarthritis, skin ulcers, skin rashes, sicca symptoms, and inflammatory myositis (IIM) it denotes severe disease. proximal muscle weakness. It should never be repeated In adults IIM Anti-Ro52 may be associated with ILD. once it is positive in significant titers. The presence of Anti-Ro antibody in pregnant lupus ANA detection by ELISA: It is of low sensitivity so is not patient may lead to congenital heart block, neonatal a preferred method for detection of ANA. lupus syndrome in fetus and may be present in ANA 6 The titer of ANA is more important than the pattern negative lupus patients and may antedate SLE by 4 years. (Figs. 1A to C). It may also be positive in subacute cutaneous lupus It may be positive in many autoimmune diseases erythematosus. and in diseases other than systemic rheumatic disease Anti-La/SSB autoantigen is present in both nucleus (Table 3). and cytoplasm but it is predominantly found in the nucleus. Anti-Ro and Anti-la Ab should be ordered when Extractable Nuclear Antigen (ENA) Profile sicca symptoms or salivary gland enlargement is present and in SLE patients who wish to become pregnant. (Table 4) If features of connective tissue disease (CTD) are present Anti-Neutrophil Cytoplasmic Antibody (ANCA) and ANA by IIFA is positive then the ENA profile should This is done by high-quality ELISA (more specific) or IIF be ordered by Immunoblot or Line immunoassay (LIA) or (more sensitive but subjective). by ELISA. ENA profile may be done in suspected Sjogren syndrome and inflammatory myositis even if ANA is ELISA: Current consensus is that in suspected ANCA negative. associated vasculitis (AAV) first high-quality antigen

MU-218.indd 1392 29-01-2021 15:23:52 Interpretation of Common Investigations in Rheumatology CHAPTER 218 1393

A B

Figs. 1A to C: ANA-IIF. (A) Homogeneous pattern (antibody against histone or dsDNA); (B) Speckled pattern (fine speckled—Ab to SS- A,SS-B, Mi2, Ku Coarse speckled—U1RNP, Sm, RNA polymerase III); (C) Centromere pattern (Ab to CENP) C Source: Dr Anuj Sharma, Consultant Pathologist, Aanvik Diagnostics, Jaipur

specific ELISA test should be done if it is negative and PR3, c-ANCA is seen in 90% cases of GPA (10% cases of clinical suspicion is strong, then repeat testing may be GPA have ANCA against MPO antigen) and has greater done by ELISA or IIF.7 specificity than p-ANCA. In limited GPA c-ANCA may Specific ELISA tests for antibodies using purified be absent. specific antigens proteinase 3 (PR3) and myeloperoxidase „„ Perinuclear ANCA (p-ANCA) (Figs. 2A and B): (MPO) are associated with higher specificities and positive ANCA is directed against MPO antigen (occasionally predictive value than IIF assays. Anti-PR3 ANCA is present against PR3). There is staining of the perinuclear in granulomatosis with polyangiitis (GPA) and Anti-MPO area leaving cytoplasm clear. ANA positive patients ANCA is present in microscopic polyangiitis (MPA). may be falsely labeled as p-ANCA positive, this can ANCA against both PR3 and MPO is seen in levamisole be avoided if IIFA tests are done with both formalin adulterated cocaine users. and ethanol fixed substrates. p-ANCA is associated with MPA (90%), renal limited vasculitis (75–80%), ANCA by IIFA (Figs. 2A and B) eosinophilic granulomatosis with polyangiitis with Using alcohol-fixed buffy coat leukocytes, there are two renal involvement, drug induced AAV and ulcerative patterns. colitis. „„ Cytoplasmic ANCA (c-ANCA) (Figs. 2): There is coarse „„ Atypical ANCA: The atypical patterns are usually granular staining of the cytoplasm. The main antigen is confused with p-ANCA patterns and may be seen in

MU-218.indd 1393 29-01-2021 15:23:55 1394 SECTION 16 Rheumatology and CTD

TABLE 3 Diseases associated with a positive ANA12

Systemic autoimmune diseases SLE Active 98–100% Remission 90% Scleroderma 95% Rheumatoid arthritis 45% Sjögren’s syndrome 60% Mixed connective tissue disease 100% Drug-induced LE 80–95% Raynaud’s phenomenon 40% Polymyositis/dermatomyositis 35% Juvenile idiopathic arthritis 15–40% Organ-specific autoimmune diseases Hashimoto’s thyroiditis 50% Graves’ disease 50% Autoimmune hepatitis 70% Primary biliary cirrhosis 50–70% Infectious diseases* Viral: EBV, HIV, HCV, Parvovirus B19 Bacterial: Subacute Bacterial Endocarditis, Syphilis Malignancies:* Lymphoproliferative diseases, Paraneoplastic syndromes Miscellaneous diseases:* Inflammatory bowel disease, Idiopathic pulmonary fibrosis SLE, systemic lupus erythematosus; EBV, Epstein-Barr virus; HCV, hepatitis C virus; *Although positive tests of ANA are reported in these diseases more often than in healthy controls, precise estimates vary. Source: Reproduced with permission from Reference 12.

immune-mediated diseases such as CTD, inflammatory Facts about ANCA: bowel disease, and autoimmune hepatitis. ELISA test „„ Negative test does not exclude the diagnosis of AAV, for PR3 or MPO is negative. sometimes biopsy is required to confirm the diagnosis. „„ Positive test does not establish the diagnosis of AAV as Indications for getting ANCA done:7 false positive may be seen in other diseases. „„ Glomerulonephritis, especially rapidly progressive „„ Titers do not correlate with severity so disease should glomerulonephritis be assessed clinically. „„ Pulmonary hemorrhage, especially pulmonary-renal syndrome Anti-phospholipid Ab (APLA) „„ Cutaneous vasculitis with systemic features Commonly three APLA are being done. „„ Multiple lung nodules 1. Lupus anticoagulant (LAC): „„ Chronic destructive disease of the upper airways Screening tests: „„ Long-standing sinusitis or otitis —— dilute Russell viper venom time (dRVVT) „„ Subglottic tracheal stenoses —— activated Partial Thromboplastin Time (aPTT) „„ Mononeuritis multiplex or other peripheral neuropathy is prolonged and fails to get corrected when the „„ Retro-orbital mass patient’s plasma is mixed with normal plasma „„ Scleritis excluding coagulation factor deficiency.

MU-218.indd 1394 29-01-2021 15:23:56 Interpretation of Common Investigations in Rheumatology CHAPTER 218 1395

TABLE 4 ENA profile

ENA antigen Antibody Clinical significance

zz Double stranded DNA zz Anti-dsDNA zz 95% Specific for SLE + in active disease & with nephritis zz Smith Ag zz Anti-Sm Ab zz Present in 10–20% SLE zz Histones (proteins of nucleosomes) zz Anti-Histone Ab zz + in drug induced lupus zz Ribosomal P protein zz Anti-Ribosomal Ab zz Specific for SLE esp. neuropsychiatric lupus

zz Ro/SSA-Ro60 (protein of cytoplasmic RNA) zz Anti-Ro/SSA (Anti-Ro60 & zz + in Sjögren syndrome 40–95% and in ANA negative SLE & Ro52 (ubiquitin ligase in cytoplasm) anti-Ro52) zz La/SSB (present in nucleus & cytoplasm) zz Anti-La/SSB zz + in 25–40% Sjögren syndrome (Both anti-Ro & anti-La associated with extraglandular manifestations*& glandular lymphocytic infiltration)

Ribonucleoprotein (RNP)—RNA + Proteins Anti-U1 RNP zz MCTD zz 40–60% SLE (not specific)

Topoisomerase-I (Scl70) zz Anti-Topoisomerase-I/ + in 30% cases of diffuse Cutaneous SSc, may be zz Anti-Scl70 associated with ILD

Centromere Anti-centromere Ab zz Limited cutaneous SSc zz Pulmonary hypertension Cytoplasmic zz Histidyl tRNA synthetases zz Anti Histidyl tRNA zz Polymyositis/Dermatomyositis, Strongly associated synthetase (Anti-Jo1) with ILD zz Ku Ag (also present in nucleus) zz Anti Ku Ab zz With overlap syndromes, e.g., myositis + SSc or SLE, UCTD zz Mitochondria zz Anti-mitochondrial Ab zz Primary biliary cirrhosis zz Smooth muscle zz Anti-smooth muscle cell Ab zz Autoimmune hepatitis RNA Polymerase III Anti RNA Polymerase III DcSSc with renal involvement PM-Scl Anti PM-Scl Systemic sclerosis *Extraglandular manifestations – Purpura, vasculitis, lymphadenopathy, leukopenia & thrombocytopenia. DcSSc, diffuse cutaneous systemic sclerosis; ILD, interstitial lung disease; UCTD, undifferentiated connective tissue disease

A B Figs. 2A and B: Antineutrophilic cytoplasmic antibody (ANCA), c-ANCA, and pANCA. IIF Staining—c-ANCA, p-ANCA Source: Dr Anuj Sharma, Consultant Pathologist, Aanvik Diagnostics, Jaipur

MU-218.indd 1395 29-01-2021 15:23:58 1396 SECTION 16 Rheumatology and CTD

TABLE 5 APLA positivity in diseases other than primary APS

ARD13 Infections Drugs (usually IgM aCL positive) (usually transient IgM aCL) zz SLE—25–50% zz Syphilis zz Cardiac—Procainamide, quinidine, zz Sjögren syndrome—42% zz Hepatitis C infection propranolol, hydralazine zz Rheumatoid arthritis—33% zz HIV infection zz Neuroleptic or psychiatric—Phenytoin, zz Autoimmune thrombocytopenic purpura—30% zz Human T-cell lymphotropic virus chlorpromazine zz Autoimmune hemolytic anemia – (Unknown) type 1 infection zz Other—Interferon alfa, quinine, zz Psoriatic arthritis28% zz Malaria amoxicillin zz Systemic sclerosis—25% zz Bacterial septicemia zz Mixed connective-tissue disease—22% zz Leptospirosis zz Polymyalgia rheumatica or giant cell arteritis—20% zz Behçet syndrome—20%

—— Kaolin clotting time syndrome, MCTD, hypocomplementemic urticarial aPTT and dRVVT may sometimes be normal if there is vasculitis, mixed cryoglobulinemia, serum sickness, acute large thrombus and it may be falsely prolonged if some glomerulonephritides including post-streptococcal the patient is on anticoagulants. nephritis. With the treatment of these diseases, C3 or 2. Anticardiolipin Ab— C4 may normalize. Low C4 with normal C3 may be seen IgG, IgM, & IgA* Done by ELISA, in hereditary angioedema and acquired C1 inhibitor not affected by Most sensitive test for APS thrombosis or oral deficiency. 3. Anti-beta-2 Glycoprotein Ab— anticoagulants IgG, IgM, & IgA* HLA B27 (*IgA isotype is included in the SLICC criteria of SLE but these are not This test is done by flow cytometry and polymerase chain routinely available in laboratories) reaction (PCR). PCR is preferred as it gives accurate results. Significant APLA titers: This test should be ordered when there are clinical features 1. aCL IgG antibody more than 40 IgG phospholipid of spondyloarthritis (SpA), viz. inflammatory backache, as (GPL) units or aCL IgM more than 40 IgM phospholipid in general population 8% population is positive for HLA (MPL) units, or more than 99th percentile (measured B27, so if ordered injudiciously a person with mechanical by ELISA) are significant.8 Titers are low (<40 GPL or backache may be wrongly diagnosed as a patient of SpA. MPL), moderate (40–80 GPL or MPL) or high (>80 GPL Ankylosing spondylitis, a subtype of SpA, 85–95% are or MPL).9 positive for this gene remaining 5–15% may be negative, 2. Anti-beta-2 glycoprotein 1 antibody of IgG and/or IgM while in SpA secondary to psoriasis or inflammatory bowel isotype in serum or plasma in titer more than 99th disease and in reactive arthritis, up to 50% may be positive 10 percentile (measured by ELISA).8 for HLA B27. False positive and false negative do occur so These tests are usually done at the time of acute judicious ordering for this test is the need. thrombotic event and must be repeated after 12 weeks to exclude false positive tests secondary to infections or Serum Uric Acid (SUA) drugs (Table 5). It is lower in females (≤6 mg%) than males (≤7 mg%). SUA is usually assessed in the diagnosis of gout but during Complement C3 and C4 acute gout flare, the levels may be normal or low in up These are measured by nephelometric immunoassay. to 40% because of release of cytokines and ACTH during Normal C3 levels range from approximately 80–160 mg/ flare, which can lower the uric acid levels. High uric levels dL. Normal C4 levels range from 16–48 mg/dL. lend support to the clinically suspected case of gout but Decreased C3 or low C3, C4 may be seen in immune its estimation is neither diagnostic nor mandatory for complex-mediated diseases, viz. SLE, APS, Sjögren’s confirmation of the diagnosis of gout.

MU-218.indd 1396 29-01-2021 15:23:58 Interpretation of Common Investigations in Rheumatology CHAPTER 218 1397

References . 1 Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed). 1983;286(6361):266. . 2 Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinic applications. Disease Markers. 2013; 35(6):727-34. 3. Saigal R, Bhakal SS, Goyal L, et al. Seroprevalence of anti-citrullinated protein antibodies (ACPA) in patients with rheumatic diseases other than rheumatoid arthritis. J Assoc Physicians India. 2018;66(4):26-8. . 4 Mahler M, Hanly JG, Fritzler MJ. Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases. Autoimmunity Reviews. 2012;11(9):642-5. 5. Haugbro K, Nossent JC, Winkler T, et a. Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity. Ann Rheum Dis. 2004;63(4):386-94. . 6 Theander E, Jonsson R, Sjöström B, et al. Prediction of Sjögren’s Fig. 3: Needle-shaped urate crystals as seen syndrome years before diagnosis and identification of patients with 11 under low power microscope early onset and severe disease course by autoantibody profiling. Arthritis Rheumatol. 2015;67(9):2427-36. 7. Bossuyt X, Tervaert J-WC, Arimura Y, et al. Revised 2017 international Synovial Fluid (SF) consensus on testing of ANCAs in granulomatosis with polyangiitis In monoarticular involvement, SF may be examined and microscopic polyangiitis. Nature Reviews Rheumatology. 2017;13:683-92. for bacteria (tubercle bacilli or non-tubercle bacilli), 8. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations fungus, and crystals. In the suspected case of gout, SF for the management of antiphospholipid syndrome in adults.Ann should be aspirated may be seen under light microscope Rheum Dis. 2019;78:1296-304. (Fig. 3)11 as polarizing microscope, which is ideal for . 9 Lopes MRU, Danowski A, Funke A, et al. Update on antiphospho­ lipid antibody syndrome. Rev. Assoc. Med. Bras. 2017;63(11):994-9. the demonstration of urate crystals, is not routinely 10. Mathiu A, Paladini F, Vacca A, et al. The interplay between the available. geographic distribution of HLA-B27 alleles and their role in infectious and autoimmune diseases: a unifying hypothesis. Autoimmunity Reviews. 2009;8(5):420-5. Conclusion 11. Saigal R, Goyal LK, Jain DK. White powder over palm: an unusual In treating ARD, it is of utmost importance that a very good presentation of hyperuricemia in polyarticular gout. J Assoc history and physical examination have been done before Physicians India. 2018;66(4):62. ordering investigations. False positives and false negatives 12. Bloch DB. Measurement and clinical significance of antinuclear do occur so one should be cautious in interpreting these antibodies. In: Post TW (Ed). UpToDate. Waltham, MA: UpToDate, investigations. “Arthritis panel” is to be avoided and should Inc.; 2020. For more information visit www.uptodate.com never be ordered. 13. Saigal R, Kansal A, Mittal M, et al. Antiphospholipid antibody syndrome. JAPI. 2010;58:176-84.

MU-218.indd 1397 29-01-2021 15:24:00