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 Anjana Pandey, Ajay Maurya, PK Maheshwari 208. Monoarthritis—A Clinical Dilemma to Internists 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 4 activity should be within 3 months of starting treatment). “pharmacokinetic refractoriness” to differentiate it from 7 It is recommended that if there is no improvement by at intrinsic refractoriness in the primary non-responders. 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.